University of Texas Medical Branch at Galveston, Departments of Internal Medicine, Physiology, and Biophysics and Pathology, Galveston, Texas 77555
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ABSTRACT |
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Myofibroblasts are a
unique group of smooth-muscle-like fibroblasts that have a similar
appearance and function regardless of their tissue of residence.
Through the secretion of inflammatory and anti-inflammatory cytokines,
chemokines, growth factors, both lipid and gaseous inflammatory
mediators, as well as extracellular matrix proteins and proteases, they
play an important role in organogenesis and oncogenesis, inflammation,
repair, and fibrosis in most organs and tissues. Platelet-derived
growth factor (PDGF) and stem cell factor are two secreted proteins
responsible for differentiating myofibroblasts from embryological stem
cells. These and other growth factors cause proliferation of
myofibroblasts, and myofibroblast secretion of extracellular matrix
(ECM) molecules and various cytokines and growth factors causes
mobility, proliferation, and differentiation of epithelial or
parenchymal cells. Repeated cycles of injury and repair lead to organ
or tissue fibrosis through secretion of ECM by the myofibroblasts.
Transforming growth factor- and the PDGF family of growth factors
are the key factors in the fibrotic response. Because of their
ubiquitous presence in all tissues, myofibroblasts play important roles
in various organ diseases and perhaps in multisystem diseases as well.
platelet-derived growth factor; stem cell factor; transforming
growth factor-; wound repair; fibrosis; inflammation; immunophysiology
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INTRODUCTION |
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A GROWING BODY OF LITERATURE over the last decade has made it evident that there is phenotypic heterogeneity among fibroblasts and that some express features of smooth muscle differentiation (73, 136, 214, 216). These smooth-muscle-like cells, or myofibroblasts as they were termed by Gabbiani (82, 83) who pioneered this field, take part in the growth, development, and repair of normal tissue as well as the diseases affecting many different organs. These cells belong to a unique class, and, even allowing for specific functions for those cells in a given organ or tissue, there is an amazing similarity in their morphology, function, and biochemical repertoire regardless of their location. Nonetheless, in a given tissue, they may express some specific appearances and functions, i.e., phenotypic and functional heterogeneity. Because of this propensity and their location next to epithelial or parenchymal cells, we have suggested they might be termed "juxtaparenchymal cells" (247).
In this review, we give an overview of myofibroblasts, illustrating similarities and differences in their biochemical/physiological/immunologic properties, and we indicate the role that these cells play in specific disease states. The major soluble factors secreted by these cells are discussed, and important receptors on myofibroblasts are listed. We have slanted the discussion toward the intestinal myofibroblasts (247): the interstitial cells of Cajal (ICC) and the subepithelial intestinal myofibroblast. This review is not meant to be entirely comprehensive of the field of myofibroblasts. It focuses on recently discovered information about the interactions of myofibroblasts with epithelial and parenchymal cells and the molecules that mediate these interactions. Furthermore, we have purposely referenced review articles when possible to amplify the reference base.
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ROLES IN HEALTH AND DISEASE |
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Table 1 lists various tissue myofibroblasts
and what is thought to be their normal function. Some of these
functions are well proven, and others can be inferred from the known
properties of myofibroblasts in other tissues. In general, there are
several common normal activities of myofibroblasts. First, through
mesenchymal-epithelial interactions, myofibroblasts are
key components of organogenesis or morphogenesis, i.e., the growth and
differentiation of the tissue or organ (227). They do so through the
secretion of soluble mediators of inflammation and growth factors
(Table 2) and expression of their receptors
(Table 3) and through secretion and
formation of interstitial matrix and/or basement membrane molecules
(Table 4) (20, 73, 82, 247). Myofibroblasts
also play a fundamental role in many disease states, either through
activation and proliferation or through deletion (Table
5) (51, 214, 216). They play a central role
in wound healing, presumably as an extension or accentuation of their
role in normal growth and differentiation (82, 83, 99, 120, 136). They
appear to be involved in the formation and repair of the extracellular
matrix (ECM) and proliferation and differentiation of epithelial (or
parenchymal), vascular and neurogenic elements (50, 215, 250, 262).
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Healing is facilitated by the fact that the myofibroblasts are contractile, which aids in reducing the amount of denuded surface area of wounded tissue (163, 192, 242). An extension of this contractile capability allows these cells to participate in the ejection of fluid from the gastric glands (237) and in the motility of intestinal villi (120). Their relationship to myoepithelial cells, which have this function in the breast lobule (204) and the seminiferous tubules of the testis (106), is unclear. The contractile property of pericytes and specialized pericytes such as the hepatic stellate (Ito) cell, the mesangial cell of the kidney, and the glomus cell of peripheral vessels gives these myofibroblasts the ability to locally autoregulate blood flow (122, 124, 160, 177, 216, 247). The ability to accumulate and extrude calcium causes cyclic increases and decreases in calcium concentration in these cells, permitting actin-myosin contraction (77). This process is probably the same as or similar to the one responsible for the ability of the ICC to perform a pacemaker function in the intestine (212). Because myofibroblasts are interconnected through gap junctions (120, 212, 246), the electrical signals created by cyclic ion movements can be transmitted through the syncytium and thus through the length of the resident organ.
Myofibroblasts play a major role in the inflammatory response. These
cells are avid producers of both chemokines and cytokines (105, 178,
179, 227, 235, 267) and are capable of augmenting or downregulating the
inflammatory response by the secretion of these soluble mediators of
inflammation (Table 2). They also synthesize prostaglandins, expressing
both the constitutive cyclooxygenase-1 (COX-1 or PHS-1) gene product
and the inducible COX-2 (PHS-2) protein (19, 69, 102, 105, 167, 240,
241, 259). In some tissues they make both nitric oxide and carbon
monoxide, gases known or proposed to be important neurotransmitters and
regulators of motility and inflammation (1, 14, 39, 69, 162, 167, 202,
240, 241). When activated, myofibroblasts also express adhesion
molecules such as intracellular adhesion molecule-1, vascular cell
adhesion molecule, and neural cell adhesion molecule (100, 133, 151,
178, 192). Thus lymphocytes, mast cells, and neutrophils may dock on
the myofibroblasts and participate in organized immunological and
inflammatory reactions (31, 48, 67, 105, 201, 236). Myofibroblasts also
express and
integrins that are part of the adhesion mechanism
of myofibroblasts to matrix proteins (192). Through these or other
properties, myofibroblasts participate in the formation of tissue
granulomas (208, 247). Granulomas themselves are impressive factories
of cytokines and other inflammatory mediators (87, 114).
Last, production of matrix molecules such as collagen, glycosaminoglycans, tenascin, and fibronectin in the interstitial space or basement membrane (Table 4) is part of the structure, growth, differentiation, and wound healing function of myofibroblasts (20, 227). These processes, when unchecked, deranged, or repeated, can result in tissue fibrosis (4, 25, 71, 72, 88, 138, 150). Therefore, fibrotic disease is a major pathological end point of activated and proliferating myofibroblasts in most, if not all, tissues.
Disease states not mentioned in Table 3 are inflammatory pseudotumors of the lung, liver, or stomach (64) and neoplastic transformation of the myofibroblasts themselves. Recent evidence indicates that stromal tumors of the gastrointestinal tract are derived from c-kit mutations in gastrointestinal myofibroblasts (103). Another benign neoplasm of myofibroblasts is the desmoid tumor, which can occur in any tissue but develops most commonly in the mesentery of the gut (92). Although desmoids can and do occur sporadically, they are particularly common (increased 850 times) in the familial adenomatous polyposis (FAP) syndrome. FAP is a hereditary malignancy presenting as colonic polyps and colorectal carcinoma (233) that is due to mutations in the adenomatous polyposis coli gene (92). Malignant myofibroblasts are also observed in clearly aggressive tumors such as angiosarcomas, fibrosarcomas, histiocytomas, and mesotheliomas (46, 216). Myofibroblasts are also responsible for the desmoplastic reaction seen in many cancers, i.e., the proliferation of fibrotic tissue within or adjacent to the tumor itself. This is most often observed in breast carcinoma, carcinoid tumors, Hodgkin's disease, and malignant melanomas (70, 153, 204, 218, 264). The role of myofibroblasts in both hereditary and nonhereditary colon cancer is discussed in more detail later in part II of this review [which will appear in the August issue (191)] (see also Ref. 131).
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DEFINITION OF A MYOFIBROBLAST |
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Myofibroblasts may be defined morphologically and immunologically through identification of expressed cytoskeletal proteins (214, 216). The simplest definition of a myofibroblast is that they are smooth-muscle-like fibroblasts. Some investigators choose to call them smooth-muscle-like cells or activated smooth muscle cells (159, 163, 237). Others refer to them as lipocytes because of their propensity to store retinoids (vitamin A) or as stellate cells, because of a shape change of transiently differentiated myofibroblasts (see below). Myofibroblasts may well represent an intermediate state between fibroblasts and smooth muscle cells. This is best demonstrated in the prostate (98, 125, 181), in the pericytes surrounding the fetal vessels of the placental stem villus (134), and in the stromal myofibroblasts of the breast (204).
In both cell culture in vitro and native tissues in situ,
myofibroblasts possess several distinguishing morphological
characteristics, some of which are present in fibroblasts or smooth
muscle cells (Fig. 1). They
display prominent cytoplasmic actin microfilaments (stress fibers), and
they are connected to each other by adherens and gap junctions (51,
239). These cells are also in contact with the ECM by focal contacts
once known as the fibronexus, a transmembrane complex made up of
intracellular contractile microfilaments and the ECM protein
fibronectin (65). Both fibronexus formation and stress fiber assembly
are regulated by Rho, a newly described member of the RAS superfamily
of small guanosine triphosphatases (GTPases) (94), specifically in
mammalian cells by Rho A. These small, monomeric GTP-binding proteins
also regulate myofibroblast morphology (191, 265). Often, an incomplete
basal lamina surrounds the myofibroblasts. Gap junctions couple some
myofibroblasts to the tissue smooth muscle, and the cells are commonly
in close apposition to varicosities of nerve fibers (134, 212, 243).
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In some tissues, e.g., the liver (Ito cells) (88), intestine
[both the ICC (243) and the subepithelial myofibroblasts] (78, 246), the orbital myofibroblast (195, 254), the synoviocyte of the
joint space (11), and brain (astrocyte) (15, 166, 193), the
myofibroblasts exist in two distinct morphological states (Fig.
2): 1)
the "activated" myofibroblast, as described above, and
2) the stellate-transformed
myofibroblast, which is considered to be a transiently differentiated
myofibroblast. This generalization, correlating appearance and
function, has not been verified in every tissue where such
morphological heterogeneity has been seen. Agents (e.g.,
prostaglandins, cholera toxin, vasoactive intestinal polypeptide) that
increase the cAMP content of activated myofibroblasts and cell-soluble
cAMP analogs themselves induce stellate transformation in vitro within
24 h (78) and stop myofibroblast proliferation (5, 119).
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Immunohistochemical characterization of myofibroblasts is based on
antibody reactions to two of the three filament systems of eukaryotic
cells (75, 116). These three systems are composed of
1) actin, a component of the
microfilaments; 2) vimentin, desmin, lamin, or glial fibrillary acidic protein (GFAP), members of the intermediate filament system; and 3)
the tubulins of the microtubules. Myofibroblasts have not been
characterized with regard to tubulins. The and
actins are
expressed by all cells, including myofibroblasts, which may also
express
-smooth muscle (
-SM) actin (214, 216). Myofibroblasts
stain negatively for
-cardiac and
-skeletal actin (216).
Myofibroblasts are not well characterized with regard to the newly
defined myosin isoforms (75, 161, 217). In some tissues, such as the
intestine and reticular cells of lymph nodes and spleen, myofibroblasts
stain positive for smooth muscle heavy chain myosin or tropomyosin (old
terminology) (216, 243).
Vimentin, desmin, and -SM actin are the three filaments most often
used to classify myofibroblasts (161). Expression of these proteins may
vary with the tissue studied within species and is subject to
environmental factors, e.g., whether the cells are studied in situ or
in culture and, even within a given tissue, whether the cells are
activated by hormonal or cytokine treatment or by disease (191). Based
on immunohistochemical staining of these filaments in a given tissue, a
classification system has been proposed (134, 216). Myofibroblasts that
express only vimentin are termed V-type myofibroblasts, those that
express vimentin and desmin are called VD-type, those that express
vimentin,
-SM actin, and desmin are called VAD-type, those that
express vimentin and
-SM actin are called VA-type, and those that
express vimentin and myosin are called VM-type.
In the intestine, the ICC express immunoreactive vimentin, -SM
actin, and smooth muscle tropomyosin, suggesting that they are members
of the V or VM (243) class of myofibroblasts. However, we have not been
able to find references indicating that ICC have been explored with
antibodies to
-SM actin. The intestinal subepithelial myofibroblasts
(ISEMFs) stain positive for vimentin and
-SM actin and negative (or
weakly) for desmin (VA-type). They also express smooth muscle myosin
(thus may be called VAM-type myofibroblasts), although expression of
myosin is less than that seen in corresponding smooth muscle cells in
the same tissue (120, 153, 246). It is possible that both intestinal
myofibroblasts, the ICC and ISEMF, could be the VA(M)-type.
Specific monoclonal antibodies have been developed to identify myofibroblasts in certain tissues. For example, the monoclonal antibody Gb42 recognizes placental myofibroblasts (134). The 8E1 monoclonal antibody reacts with many of the stellate-shaped myofibroblasts, such as GFAP-positive astrocytes, and both intestinal myofibroblasts, the ICC and ISEMF (79). Anti-GFAP serum stains astrocytes, pancreatic periacinar stellate cells, and hepatic stellate (Ito) cells (30). The PR2D3 antibody stains subepithelial myofibroblasts in the stomach and intestine, lung myofibroblasts, periductular myofibroblasts of the kidney, testes, and breast, Ito cells of the liver, umbilical cord stellate myofibroblasts, and both vascular and tissue smooth muscle of most organs (199). Antibodies against the protooncogene c-kit, the receptor for stem cell factor (SCF or steel factor), react with ICC (109, 132, 244) and possibly with pulmonary alveolar myofibroblasts (61). No systematic studies have been reported concerning the reactivity of all the other myofibroblasts to c-kit antibodies.
In many of the studies quoted above, only a subset of the
(myo)fibroblasts stain with -SM actin antibodies in vivo or in vitro
(culture). In vivo, not all fibroblastic-appearing cells are
myofibroblasts. In culture, treatment with transforming growth factor-
(TGF-
) may induce uniform
-SM actin staining of all the cells, providing the cells are of a single clone (226).
Furthermore, activation to an
-SM actin-expressing
phenotype may require both TGF-
and a specific cell-matrix
interaction (118, 222) (see ACTIVATION, PROLIFERATION, AND
MIGRATION OF MYOFIBROBLASTS).
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ORIGIN OF MYOFIBROBLASTS AND ROLE IN GROWTH AND DEVELOPMENT |
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It is unclear whether myofibroblasts originate from progenitor stem
cells (possibly neuroepithelial stem cells) (24, 157) from the neural
crest (117) or simply transdifferentiate from resident tissue
fibroblasts (81) or from tissue (e.g., vascular, intestinal, or
uterine) smooth muscle cells (204). The close anatomic relationship of
pericytes to vascular smooth muscle and of intestinal myofibroblasts to
intestinal smooth muscle suggests a bidirectional route of
transdifferentiation. These various possibilities are depicted in Fig.
3. It has recently been suggested that
renal tubular cells (a cell of endoderm origin) might differentiate into myofibroblasts (mesenchymal cells) under noxious stimuli (171,
177, 198). However, it is equally likely that the peritubular interstitial myofibroblasts are proliferating under these circumstances and simply replacing apoptotic tubular cells in these disease states.
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Two soluble factors have been shown to promote differentiation from
embryonic stem cells: PDGF and SCF. PDGF has two chains, A and B, and
exists as a homodimer (PDGF-AA or PDGF-BB) or as a heterodimer
(PDGF-AB). Each form acts on separate receptors: receptors that are
nondiscriminatory and can bind AA, BB, and AB dimers or
receptors
that are specific for the B chain (126). After ligand binding, there
are two separate intercellular signaling pathways for the PDGF
receptor: a mitogen-activated protein kinase (MAPK) path and one
involving phosphatidylinositol 3-kinase (PI3K). Depending on the cell
types, one pathway may be required for cell activation and/or
proliferation and the other pathway for cell motility (migration) (3,
72, 150). For example, smooth muscle cells proliferate in response to
the MAPK cascade and migrate in response to the PI3K path, whereas
hepatic stellate cells and endothelial cells respond with both
proliferation and migration via the PI3K (72).
Disruption of the PDGF-AA gene in mice is lethal in 50% of affected animals (26). The surviving animals are almost completely devoid of lung alveolar myofibroblasts (also called pulmonary contractile interstitial cells) and develop emphysema due to failure of lung septation. In contrast, animals born with disruption of the PDGF-BB gene have a virtual absence of renal mesangial cells and failure of the formation of the complex structure of the glomerulus (141, 234). The PDGF-BB-deficient animals also lack pericytes and thus develop microaneurysms, reminiscent of those seen in the diabetic retina, and leaky vessels that cause tissue edema and hemorrhage (142). Intestinal subepithelial myofibroblasts (119) and hepatic stellate cells (147) proliferate in response to low concentrations of PDGF-BB, suggesting that this growth factor is important in the growth and development of these cells.
The protooncogene c-kit is the transmembrane glycoprotein tyrosine kinase (III) receptor (160 kDa molecular mass) for SCF, a growth factor secreted by epithelial cells, white blood cells, and (myo)fibroblasts. SCF is also a member of the PDGF family, and the tyrosine kinase type III family also includes receptors for granulocyte/macrophage colony-stimulating factor (GM-CSF). Intestinal ICC (in situ and in culture) express c-kit as detected by rat anti-kit (ACK2) monoclonal antibodies (18, 109, 132, 174, 244). Mutations in the c-kit locus, the W mutants, result in abnormalities in the number, structure, and function of the ICC (18, 52, 174, 212, 249). Furthermore, mutants of the ligand SCF, steel (Sl) mutants, also show morphological and functional abnormalities of the ICC (257). Thus the PDGF family of growth factors seems crucial for the embryological development of myofibroblasts. Unfortunately, no systematic study of the various different tissue myofibroblasts has been reported in PDGF or SCF knockout mice or in mutants of their respective receptors.
TGF-, PDGF, insulin-like growth factor II (IGF-II), and
interleukin-4 (IL-4) appear to be the most important growth factors for
the transdifferentiation of fibroblasts to myofibroblasts or of
stellate-transformed myofibroblasts into activated myofibroblasts (45,
61, 145, 211, 239). When myofibroblasts from the intestine (74), breast
(203), skin (17, 111, 263), liver (88), lung (214), prostate (181),
nose (256), and joint synovium (214) are treated with TGF-
in
serum-containing media, they express
-SM actin, reduce the number of
vitamin A lipid droplets, and expand the rough endoplasmic reticulum,
i.e., they take on the morphology of an activated myofibroblast.
Conversely, interferon (IFN)-
and IFN-
(56, 90) decrease the
expression of
-SM actin in myofibroblasts. It is not clear whether
they do so by transdifferentiating myofibroblasts back to the
fibroblast state, inducing them to undergo stellate transformation, or
simply downregulating the amount of
-SM actin in the cell.
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ACTIVATION, PROLIFERATION, AND MIGRATION OF MYOFIBROBLASTS |
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Fibroblasts or stellate-transformed myofibroblasts become activated and
proliferate when cultured on plastic in serum-containing growth culture
media, especially when seeded at low cell density (74, 155). In vivo
activation, as signified by the development of -SM actin positivity,
may be separable from proliferation. Whereas many fibrogenic cytokines
[IL-1, tumor necrosis factor (TNF)-
, PDGF, fibroblast growth
factor (FGF), and TGF-
] have been incriminated in this process
(138), TGF-
appears to be the most important cytokine causing the
development of
-SM actin staining and an activated phenotype (25,
45, 88, 97, 155, 165, 223, 238) capable of collagen secretion (25, 45,
165). The source of TGF-
in damaged tissue may be from white blood cells, parenchymal or epithelial cells, or from the myofibroblast itself in an autocrine fashion (22, 25, 45, 88). Recently, it has been
determined that the activation of the myofibroblast requires the
presence of matrix molecules, specifically, the ED-A (EIIIA) domain of
fibronectin (118, 222). Tissue injury gives rise to this specific ED-A
domain splice variant of fibronectin. ED-A is the binding site for cell
membranes and for other matrix molecules. It has been shown in both
skin granulation tissue (222) and hepatic (118) models that this
fibronectin ED-A domain is necessary for TGF-
to trigger
-SM
actin expression and collagen secretion by myofibroblasts. Following
activation of the myofibroblast, PDGF or connective tissue growth
factor (CTGF), a member of the PDGF family (29), appears to be the
factor primarily responsible for myofibroblast proliferation (71, 72,
89, 119, 147). TGF-
was once considered the prime factor (88, 214,
216), but it is now thought that TGF-
acts predominantly through the induction of PDGF receptors on or synthesis of CTGF by the
myofibroblasts (72, 89, 111, 112, 263). Thus TGF-
is predominantly a cytodifferentiating rather than a proliferating growth factor.
The TGF-s are a large superfamily of soluble factors important in
growth, development, and fibrogenesis (149). TGF-
1, TGF-
2, and
TGF-
3 are encoded from three separate genes. TGF-
1 is the isoform
usually upregulated in the presence of tissue injury. It is secreted in
a latent form after cleavage from a large promolecule and then
noncovalently binds to another peptide on the cell membrane called the
latency-associated peptide, which, in turn, is formed from the cleavage
fragments of the TGF-
precursor. This latent TGF-
is stored on
the surface of the cell or on the extracellular matrix, awaiting
conversion by unknown mechanisms to active TGF-
. In contrast to
their apparent (but probably indirect) proliferative effect on
myofibroblasts (see above), TGF-
s cause
G1 phase cell cycle arrest of
epithelial and smooth muscle cells and may even induce apoptosis (25).
TGF-
acts through a superfamily of serine-threonine kinase cell
surface receptors. All three TGF-
s bind first to the type II (RII)
receptor that assembles and phosphorylates the type I (RI) receptor,
activating this serine-threonine kinase and transducing the signal
(25). Microsatellite (genomic) instability due to defects in DNA
mismatch repair systems of the TGF-
receptors has been incriminated
in the unregulated growth of cancer and in vascular
atherosclerosis/restenosis (159). This raises the question of a role
for myofibroblasts in these two diseases [see part II of this review
(191)].
TGF- (138), a member of the epidermal growth factor (EGF) family, as
well as EGF itself (138, 214, 216, 226), GM-CSF (25), both acidic and
basic FGF (aFGF and bFGF, respectively) (25, 119, 185, 214, 216, 226),
and IGF-I and IGF-II (25, 226) are candidate growth factors promoting
myofibroblast proliferation (see more details in Growth
Factors). Proinflammatory cytokines such as TNF-
,
IL-1, IL-6, and IL-8 may also cause activation and proliferation (119,
138, 177, 185, 246) as does IL-4, a protein generally thought of as an
anti-inflammatory cytokine (61, 156, 211).
ANG II or aldosterone, thrombin, and endothelin are also important soluble factors reported to promote myofibroblast activation (15, 34, 35, 77, 246, 258). Endothelin is capable of rapidly transdifferentiating the stellate morphology of intestinal myofibroblasts to the activated phenotype within 30 min of addition to cell culture media (78, 80, 246). After it activates the myofibroblasts, endothelin may subsequently inhibit their proliferation (147, 148).
Cocultures of fibroblasts and myofibroblasts with cancer cells of
several different types induce transdifferentiation of fibroblasts to
myofibroblasts and activation and proliferation of myofibroblasts (13,
19, 46, 70, 136, 149, 153, 204, 246, 264). This property of neoplastic
cells, perhaps via secretion of growth hormones such as TGF-, may
well be responsible for the desmoplastic reaction (excessive fibrosis)
seen in many cancers.
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ROLE IN WOUND REPAIR |
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The process of wound healing is a highly orchestrated event that entails the release of proinflammatory cytokines, eicosanoids of the cyclooxygenase, lipoxygenase, and cytochrome P-450 family, nitric oxide, and a host of growth factors; the secretion of collagen and other matrix proteins; the elaboration of angiogenic, angiostatic, and nerve growth factors; and, finally, if it is a deep or open wound, the formation of granulation tissue that then becomes a scar (fibrosis) (20, 57, 187, 208, 214, 247, 252). Myofibroblasts appear to be key cells in these various events. They become activated and proliferate in the early stages of wounding. They respond to proinflammatory cytokines with elaboration of matrix proteins and additional growth factors and then disappear by apoptosis following repair or scar formation (51, 54, 55, 113, 164, 266).
Repair Processes
Epithelial tissues such as the intestine or stomach, in contrast to organs such as the liver, kidney, or lung, do not commonly sustain widespread injury that leads to uniform fibrosis. However, gastrointestinal epithelial tissues are often superficially injured. In fact, exfoliation of the epithelium is viewed as a defense response to certain noxious insults such as toxins, microbiological invasion, or gut anaphylaxis (163). The process of repair of the epithelium occurs through two separate mechanisms (252). If the basement membrane underlying the sloughed epithelium is intact, residual epithelial cells at the edges of the wound become motile and move along the basement membrane until they meet advancing epithelial cells from the other side of the wound and form new tight junctions. This process is called restitution (189, 225). Prostaglandins from COX-1 or COX-2 activation are key factors promoting restitution (23) and preserving the epithelial cells from damage (47). Myofibroblast-secreted growth factors such as TGF-Conversely, if the wound is deep, the subepithelial tissues that contain interstitial substance, blood vessels, nerves, and fibroblasts must be reconstituted. If the basement membrane has been destroyed by the noxious stimulus, epithelial cells and mesenchymal elements form a new basement membrane (252). Epithelial stem cells then undergo mitosis and proliferate and migrate along the newly formed basement membrane. This latter process is a coordinated event involving secretion of matrix proteins and growth factors. Thus myofibroblasts appear to play roles both in the restitution and repair processes.
A key event in the process of wound repair by either restitution or
proliferation is contraction of the underlying granulation tissue or
gastrointestinal lamina propria to limit the exposed surface area of
the wound (51, 120, 163, 192, 208, 242). Myofibroblasts contain smooth
muscle myosin isoforms in addition to -SM actin, the requisite
machinery for contraction and/or motility. The ability of
myofibroblasts to carry out these processes depends on changes in the
cellular cytoskeleton as well as in the Rho-regulated fibronexus and on
the expression of integrins that allow attachment of the myofibroblasts
to the extracellular matrix (192, 242).
The fibronexus, discovered and characterized by Eyden (65) and Singer
and colleagues (228-232) connects the myofibroblast to the
extracellular matrix through a transmembrane integrin complex that joins the actin stress fiber of the myofibroblast to ECM fibronectin (32, 192). The Rho family of small GTPases includes Rac
1-3, Cdc 42, and Rho A-H, which respond to PDGF, TNF-
or bradykinin, or lipopolysaccharide A, respectively. In mammals, Rho A
acts on the actin cytoskeleton to cause myofibroblast shape change or
motility (6, 265).
ECM
The ECM is a complex mixture of collagen, other glycoproteins, and proteoglycans distributed in each organ or tissue in unique proportions (220, 227). These matrix proteins have several general functions: they are the scaffold for tissue formation and growth; through binding to cell receptors (integrins), they initiate intercellular signaling events; and they bind to growth factors and thus supply sustained concentration of these factors for epithelial or parenchymal cell migration, proliferation, and differentiation (20, 219, 227). There are at least 19 different collagens in the collagen superfamily, with types I, III, IV, and VIII being secreted by myofibroblasts (154, 168). Proteoglycans are proteins with large sulfated polysaccharide side chains of several types (Table 4). The major glycoproteins secreted by the myofibroblasts are the various laminins, which include fibronectin (see ACTIVATION, PROLIFERATION, AND MIGRATION OF MYOFIBROBLASTS) and tenascin. Laminin is a constituent of the basement membrane along with type IV collagen, entactin, and chondroitin sulfate (all of mesenchymal origin) and perlecan, a large, low-density proteoglycan composed of heparan sulfate side chains of epithelial cell origin (20, 227). Basement membranes and matrix are degraded by a family of Zn2+-dependent matrix metalloproteinases (MMPs 1-3) also secreted by myofibroblasts (146, 251). They are classified by the substrates they degrade: MMP 1 digests types I, II, and III collagen; MMP 2 (gelatinase A) digests denatured collagens I and III and native collagen IV; and MMP 3 (stromelysin) degrades laminin, fibronectin, proteoglycans, type IV collagen, and casein (16, 251). These MMPs are inhibited by tissue inhibitors of metalloproteinases (TIMPs) (16). Growth factors may bind to heparan sulfate proteoglycans or collagen, thus controlling their availability both temporally and spatially, and so modify their biological activity (20, 219, 227, 242).Growth Factors
The growth factors secreted by myofibroblasts have three general functions as follows: 1) they initiate or increase cell mobility, 2) they induce proliferation, i.e., they are paracrine mitogens for epithelial or parenchymal cells and perhaps autocrine mitogens for themselves, or 3) they induce terminal differentiation of these cells, even driving the cells to apoptosis. Some growth factors seem to have all three effects.Individual growth factors may be produced by the epithelial cells alone
(trefoil proteins), by mesenchymal cells such as myofibroblasts or
inflammatory cells, particularly macrophages and lymphocytes, and some
by both cell types (67). Furthermore, the various inflammatory cytokines, eicosanoids, and growth factors released during tissue damage may directly affect the epithelium or parenchymal cell of the
injured tissue, or these agents may act more proximally on
myofibroblasts to induce these cells to secrete additional cytokines,
eicosanoids, or growth factors (67). Thus an in vivo epithelial
proliferative response could be the result of a cytodifferentiating effect of mediators on the myofibroblasts, inducing them to express receptors for other factors or to secrete specific epithelial proliferating growth factors. Examples of this are TGF-1, which induces the expression of PDGF receptors on or CTGF secretion by the
myofibroblasts, causing them to proliferate in response to PDGF (137),
or the secretion of hepatocyte growth factor (HGF) or keratinocyte
growth factor (KGF) by myofibroblasts in response to IL-1 (37) or
immune stimulation (10, 66).
IL-1 (60), IL-6 (261), IL-15 (196), and TNF- (121, 139) have also
been identified as being involved in tissue repair and
have been shown to be mitogenic for several mesenchymal and epithelial
cell lines. Furthermore, combinations of cytokines and growth factors
may have offsetting effects on epithelial proliferation, so the
ultimate consequence of these various factors in vivo can be quite complicated.
Factors secreted by myofibroblasts such as EGF and TGF- (12, 188),
IGF-I and IGF-II (144, 145), HGF (28, 84, 173), and members of the FGF
family, including aFGF, bFGF (also known as FGF-2) (110), KGF (also
known as FGF-7) (107, 207), and IL-11 (38, 175, 194), have been
demonstrated to be the major paracrine growth factors for epithelial
and parenchymal cells. The trefoil peptides, secreted by the epithelial
cells themselves, have similar effects through autocrine stimulation
(186). These factors may also have nonmitogenic effects on intestinal
cells as well, e.g., they may regulate secretory and contractile
processes as well as regulate blood flow (245).
The trefoil peptides are so named because of a distinctive pairing of six cysteine residues that results in three interchained loops, thus giving a "three leaf" trefoil shape (38, 186). There are three such trefoil proteins that are small, highly stable molecules secreted principally by the goblet (mucus)-secreting cells of the epithelium and not by myofibroblasts. The stomach secretes peptide pS2 in the fundus and spasmolytic polypeptide (SP) in the antrum, whereas the breast epithelium secretes only pS2 and the pancreas secretes only pancreatic SP (pSP) (129). In contrast, the intestinal epithelium secretes only intestinal trefoil factor (ITF). Targeted gene disruption of ITF causes abnormal epithelial cells and increased susceptibility to various models of injury, resulting in a colitis-like picture (7, 130). Exogenous administration of ITF repairs the damage susceptibility in this knockout model and also protects the gastric mucosa against other injuries such as those induced by ethanol or chronic indomethacin administration (7). PS2 gene knockout mice have a different disease phenotype; they develop extensive neoplastic adenomas in the antrum of the stomach, which then progress to carcinoma in situ (140).
TGF-, EGF, and the EGF human homologue urogastrone (EGF/URO) are
members of the same family of polypeptides and act on a common cell
membrane receptor (12, 188). The TGF-
/EGF receptor appears to be
upregulated in the mucosa of injured intestine and other organs.
TGF-
is expressed in epithelial cells, myofibroblasts, and
monocytes/macrophages, whereas EGF seems to be produced primarily by
the epithelial cells of the salivary gland and Brunner's glands of the
duodenum. TGF-
is synthesized as a 160-amino acid precursor molecule
that spans the cell membrane. Proteases release the soluble 50-amino
acid form. It is unclear whether the membrane-bound form is active as a
growth factor for adjacent cells. The soluble factor is trophic
(mitogenic) for a number of cell lines in vitro and intestinal
epithelial cells in vivo. It may well have differentiating functions as
well. Ulceration of the human gastrointestinal mucosa causes the
development of a specific cell lineage from epithelial stem cells that
bud from the crypts next to an ulcer and then ramify to form a small
gland. These budding glands secrete EGF/URO, which stimulates
epithelial proliferation and promotes ulcer healing (260).
The FGF family (aFGF and bFGF) are important mitogens for myofibroblasts and have powerful neurotrophic and angiogenic properties that are important for tissue healing (68, 110). Other angiogenic factors secreted by myofibroblasts include the CXC family of cytokines such as IL-8 and epithelial neutrophil-activating peptide (ENA-78) (5, 127, 178). Cell-to-cell contact such as that occurring in restitution or wound healing has its antiapoptotic action via the adhesion molecule N-cadherin. When the adjacent cells touch, there is homophilic binding of N-cadherin molecules, which activate the FGF family of receptors. In this way, cell contact mimics the antiapoptotic effect of bFGF (91).
IGF-I and IGF-II are structurally related polypeptides that have various metabolic, proliferative, and differentiating effects through endocrine, autocrine, and paracrine mechanisms (144, 145). The effects are mediated by IGF-I receptors and insulin receptors. There is an IGF-II receptor, but its role in signal transduction is unclear. IGF is present in the circulation (from liver) and is also secreted in a paracrine fashion by myofibroblasts adjacent to epithelial and parenchymal cells (144). The IGF actions are determined by the availability of free IGF, the form that interacts with its receptors. In turn, the amount of free IGF is modulated by the level of high-affinity IGF-binding proteins (IGFBPs), of which six have been identified (42-44). These IGFBPs not only regulate the bioavailability of IGF but also inhibit or enhance its action on target tissues. Although the IGFs are weakly mitogenic for epithelial and parenchymal cells, they seem to be powerfully mitogenic for myofibroblasts (226) and other smooth muscle cells (255).
A new member of the family of factors stimulating epithelial growth is
IL-11, a multifunctional cytokine originally derived from bone marrow
stromal cells (175, 194). It regulates the growth of hematopoietic and
lymphoid cells by acting on the IL-6 family of cytokine receptors. It
stimulates proliferation of small intestinal crypts and accelerates
recovery of the intestinal mucosa from models of damage (143). It also
has trophic effects on neurons, preadipocytes, and myofibroblasts of
the lung (175). TGF- and IL-1 are potent stimulants of IL-11
production. Paradoxically, IL-11 has been shown to inhibit epithelial
cell proliferation in the lung by altering phosphorylation of the
retinoblastoma protein (194). Thus it is possible that the
proliferative effect of IL-11 on epithelia occurs via activation of
myofibroblasts, with subsequent secretion of epithelial proliferating
factors by these cells, rather than being a direct effect of IL-11 on the epithelium itself.
KGF is a member of the FGF family (FGF-7) (107, 207). This factor is unique because, unlike other members of the FGF family, it does not appear to have activity on fibroblasts, endothelial cells, or other nonepithelial targets. This is a consequence of the epithelial cell expression of the KGF receptor (KGFR), a transmembrane tyrosine kinase that binds KGF and aFGF with high affinity and binds bFGF much more poorly. The KGFR is nearly identical to the FGF receptor type II, except for alterations in a 49-amino acid residue in one of its extracellular loops. FGFR-II does not bind KGF but shows a high affinity for both aFGF and bFGF. KGFR expression is limited to epithelial cells, whereas FGFR-II is present in a variety of tissues including fibroblasts. KGF, initially isolated from lung fibroblasts, appears to be a myofibroblast-secreted epithelial growth factor with specific roles in epithelial growth and differentiation. The KGFR is expressed on the epithelial cells, and KGF has been shown to induce proliferation and differentiation of a host of epithelial and parenchymal cells, including intestinal epithelial cells, type II pneumocytes, hepatocytes, and keratinocytes of the skin. Its expression and secretion are regulated by IL-1 (37). Its synthesis is significantly upregulated in the lamina propria of inflamed intestine (66). Thus KGF represents a prime example of a mediator causing a specific mesenchymal-epithelial interaction.
HGF, also known as scatter factor because it induces cell migration as
well as proliferation, is synthesized and secreted by fibroblasts and
myofibroblasts (28, 84). HGF is a glycoprotein heparin-binding
heterodimer related to plasminogen, consisting of a heavy chain and
a light
chain held together by disulfide bonds (84).
It is produced as a single-chain precursor protein and proteolytically
cleaved to form HGF. The HGF receptor, prominently expressed by
epithelial cells, is encoded by the protooncogene c-met. This receptor is a
heterodimeric glycoprotein of 190 kDa linked with two disulfide bonds;
the
chain is extracellular, while the membrane-spanning
chain
has the cytoplasmic domain of a tyrosine kinase.
C-met also is regulated by proteases
that cleave both chains from a 178-kDa common precursor. Thus HGF is only active if the correct proteases are present. Like TGF-
, HGF has
effects on cell division, motility, and apoptosis and appears to have
angiogenic activity (28). Its synthesis is stimulated by IL-1 (28). Not
only does it cause proliferation of epithelial cells but it also
affects parenchymal cells such as liver and bone (28). Thus HGF, like
KGF, is a major mediator of epithelial-mesenchymal interactions and
epithelial morphogenesis (207).
The process of repair is completed by the terminal differentiation of
epithelial and parenchymal cells and by apoptosis of the -SM actin
myofibroblasts (51, 81, 216). The factors that terminate the repair
process are poorly understood. The role of IL-10, INF-
, and INF-
in either the downregulation (90, 197) of myofibroblasts or induction
of their apoptosis (95, 128) needs further investigation.
![]() |
ROLE IN FIBROSIS |
---|
With repeated cycles of injury and repair or if, for unclear reasons,
there is loss of the signals that discontinue the healing process,
organ fibrosis occurs. The important functions of the myofibroblasts in
the fibrosis of tissues such as the skin, lung, pancreas, and kidney
are well described (see references in Table 4). The effects of PDGF,
TGF-, and other growth factors in the fibrotic process have been
studied in detail (72, 93, 167, 214, 239) and are beyond the scope of
this review (see Refs. 20 and 96 for detailed reviews of fibrosis).
Factors that act on myofibroblasts are important in tissue fibrosis.
Recently, the key role of TGF- in fibrosis has been accentuated by
the finding of fibrosis of multiple organs, including the liver, kidney
(both renal interstitium and glomerulus), and adipose tissue in a
transgenic mouse overexpressing TGF-
(45). PDGF-BB causes fibrosis
in the kidney (239), and, given the propensity of TGF-
to upregulate
PDGF receptors, an equally important role for PDGF cannot be ruled out.
IGF-I has been shown also to induce collagen mRNA and IGF binding
protein-5 mRNA in rat intestinal smooth muscle (269), raising the
question of an important role for this growth factor in organ
fibrogenesis (268). IL-1, IL-6, INF-
, TNF-
, and bFGF have also
been incriminated as fibrogenic cytokines (101, 205). Potential
abnormalities in matrix secretion, degradation of matrix by MMPs, and
inhibition of MMPs by TIMPs (see above) that might result in fibrosis
are under investigation (21, 96, 154). An understanding of these
processes and the development of effective pharmacological or
biological inhibitors would be important advances in the treatment of disease.
![]() |
CONCLUSIONS AND SPECULATION |
---|
Myofibroblasts are ubiquitous cells with similar properties and
functions that play important roles in growth and development, wound
repair, and disease. Either their absence or their activation and
proliferation in a given tissue or organ can lead to specific diseases
as outlined in Table 3. However, because they are present in virtually
every tissue, it is possible that they may play a role in multisystem
diseases as well. For example, do abnormalities in pericytes account
for some of the multifocal effects of chronic hypertension (208)? Are
the multiple abnormalities of diabetes mellitus due to stimulation of
or damage to vascular, renal, intestinal, and skin myofibroblasts? It
is intriguing that high glucose concentrations induce TGF-1
production by the glomerular mesangial cell (135), and PDGF and bFGF
improve wound healing in genetically diabetic animals (87). What is the
role of myofibroblasts in aging, a condition in which myofibroblasts
are reported to be morphologically abnormal (169)? These are but a few
of the intriguing questions raised by this unique family of pleiotropic cells.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Terri Kirschner for excellent editorial expertise.
![]() |
FOOTNOTES |
---|
We acknowledge the support of National Institute of Diabetes and Digestive and Kidney Diseases Grant 2 R37 DK-15350, a grant from the Crohn's and Colitis Foundation of America, and support from The Keating Fund for Research Prevention of Cancer, administered by the University of Texas Medical Branch (UTMB) Small Grants Program, UTMB at Galveston.
Address for reprint requests and other correspondence: D. W. Powell, Dept. of Internal Medicine, Univ. of Texas Medical Branch at Galveston, 4.108 John Sealy Annex 0567, 301 Univ. Blvd., Galveston, TX 77555-0567 (E-mail: dpowell{at}utmb.edu).
![]() |
REFERENCES |
---|
1.
Acevedo, C. H.,
and
A. Ahmed.
Hemeoxygenase-1 inhibits human myometrial contractility via carbon monoxide and is upregulated by progesterone during pregnancy.
J. Clin. Invest.
101:
949-955,
1998
2.
Aigner, T.,
D. Neureiter,
S. Muller,
G. Kuspert,
J. Belke,
and
T. Kirchner.
Extracellular matrix composition and gene expression in collagenous colitis.
Gastroenterology
113:
136-143,
1997[Medline].
3.
Anand-Apte, B.,
B. R. Zetter,
A. Viswanathan,
R. G. Qiu,
J. Chen,
R. Ruggieri,
and
M. Symons.
Platelet-derived growth factor and fibronectin-stimulated migration are differentially regulated by the Rac and extracellular signal-regulated kinase pathways.
J. Biol. Chem.
272:
30688-30692,
1997
4.
Apte, M. V.,
P. S. Haber,
T. L. Applegate,
I. D. Norton,
G. W. McCaughan,
M. A. Korsten,
R. C. Pirola,
and
J. S. Wilson.
Periacinar stellate shaped cells in rat pancreas: identification, isolation and culture.
Gut
43:
128-133,
1998
5.
Arenberg, D. A.,
M. P. Keane,
B. DiGiovine,
S. L. Kunkel,
S. B. Morris,
Y. Y. Xue,
M. D. Burdick,
M. C. Glass,
M. D. Iannettoni,
and
R. M. Strieter.
Epithelial neutrophil-activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer.
J. Clin. Invest.
102:
465-472,
1998
6.
Aspenstrom, P.
The Rho GTPases have multiple effects on the actin cytoskeleton.
Exp. Cell Res.
246:
20-25,
1999[Medline].
7.
Babyatsky, M. W.,
M. deBeaumont,
L. Thim,
and
D. K. Podolsky.
Oral trefoil peptides protect against ethanol- and indomethacin-induced gastric injury in rats.
Gastroenterology
110:
489-497,
1996[Medline].
8.
Bachem, M. G.,
E. Schneider,
H. Gross,
H. Weidenbach,
R. M. Schmid,
A. Menke,
M. Siech,
H. Beger,
A. Grunert,
and
G. Adler.
Identification, culture, and characterization of pancreatic stellate cells in rats and humans.
Gastroenterology
115:
421-432,
1998[Medline].
9.
Bahn, R. S.
The fibroblast is the target cell in the connective tissue manifestations of Graves' disease.
Int. Arch. Allergy Immunol.
106:
213-218,
1998.
10.
Bajaj-Elliott, M.,
R. Poulsom,
S. L. Pender,
N. C. Wathen,
and
T. T. Macdonald.
Interactions between stromal cell-derived keratinocyte growth factor and epithelial transforming growth factor in immune-mediated crypt cell hyperplasia.
J. Clin. Invest.
102:
1473-1480,
1998
11.
Baker, D. G.,
J. Dayer,
M. Roelke,
H. R. Schumacher,
and
S. M. Krane.
Rheumatoid synovial cell morphologic changes induced by a mononuclear cell factor in culture.
Arthritis Rheum.
26:
8-14,
1983[Medline].
12.
Barnard, J. A.,
R. D. Beauchamp,
W. E. Russell,
R. N. DuBois,
and
R. J. Coffey.
Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology.
Gastroenterology
108:
564-580,
1995[Medline].
13.
Barsky, S. H.,
W. R. Green,
G. R. Grotendorst,
and
L. A. Liotta.
Desmoplastic breast carcinoma as a source of human myofibroblasts.
Am. J. Pathol.
115:
329-333,
1984[Abstract].
14.
Bauer, I.,
G. A. Wanner,
H. Rensing,
C. Alte,
E. A. Miescher,
B. Wolf,
B. H. Pannen,
M. G. Clemens,
and
M. Bauer.
Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver.
Hepatology
27:
829-838,
1998[Medline].
15.
Beecher, K. L.,
T. T. Andersen,
J. W. Fenton,
and
B. W. Festoff.
Thrombin receptor peptides induce shape change in neonatal murine astrocytes in culture.
J. Neurosci. Res.
37:
108-115,
1994[Medline].
16.
Benyon, R. C.,
J. P. Iredale,
S. Goddard,
P. J. Winwood,
and
M. J. Arthur.
Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver.
Gastroenterology
110:
821-831,
1996[Medline].
17.
Berndt, A.,
H. Kosmehl,
U. Mandel,
U. Gabler,
X. Luo,
D. Celeda,
L. Zardi,
and
D. Katenkamp.
TGF beta and bFGF synthesis and localization in Dupuytren's disease (nodular palmar fibromatosis) relative to cellular activity, myofibroblast phenotype and oncofetal variants of fibronectin.
Histochem. J.
27:
1014-1020,
1995[Medline].
18.
Bernex, F.,
P. De Sepulveda,
C. Kress,
C. Elbaz,
C. Delouis,
and
J. J. Panthier.
Spatial and temporal patterns of c-kit-expressing cells in WlacZ/+ and WlacZ/WlacZ mouse embryos.
Development
122:
3023-3033,
1996
19.
Berschneider, H. M.,
and
D. W. Powell.
Fibroblasts modulate intestinal secretory responses to inflammatory mediators.
J. Clin. Invest.
89:
484-489,
1992[Medline].
20.
Birchmeier, C.,
and
W. Birchmeier.
Molecular aspects of mesenchymal-epithelial interactions.
Annu. Rev. Cell Biol.
9:
511-540,
1993.
21.
Bissell, D. M.,
and
J. J. Maher.
Hepatic fibrosis and cirrhosis.
In: Hepatology: A Textbook of Liver Disease, edited by D. Zakim,
and T. D. Boyer. Philadelphia, PA: Saunders, 1996, p. 506-525.
22.
Bissell, D. M.,
S. S. Wang,
W. R. Jarnagin,
and
F. J. Roll.
Cell-specific expression of transforming growth factor- in rat liver. Evidence for autocrine regulation of hepatocyte proliferation.
J. Clin. Invest.
96:
447-455,
1995[Medline].
23.
Blikslager, A. T.,
M. C. Roberts,
J. M. Rhoads,
and
R. A. Argenzio.
Prostaglandins I2 and E2 have a synergistic role in rescuing epithelial barrier function in porcine ileum.
J. Clin. Invest.
100:
1928-1933,
1997
24.
Bockman, D. E.,
and
G. S. Sohal.
A new source of cells contributing to the developing gastrointestinal tract demonstrated in chick embryos.
Gastroenterology
114:
878-882,
1998[Medline].
25.
Border, W. A.,
and
N. A. Noble.
Transforming growth factor in tissue fibrosis.
N. Engl. J. Med.
331:
1286-1292,
1994
26.
Bostrom, H.,
K. Willetts,
M. Pekny,
P. Leveen,
P. Lindahl,
H. Hedstrand,
M. Pekna,
M. Hellstrom,
S. Gebre-Medhin,
M. Schalling,
M. Nilsson,
S. Kurland,
J. Tornell,
J. K. Heath,
and
C. Betsholtz.
PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis.
Cell
85:
863-873,
1996[Medline].
27.
Boya, J.,
A. L. Carbonell,
and
A. Martinez.
Myofibroblasts in human palatal mucosa.
Acta Anat. (Basel)
131:
161-165,
1988[Medline].
28.
Bradbury, J.
A two-pronged approach to the clinical use of HGF.
Lancet
351:
272,
1998[Medline].
29.
Bradham, D. M.,
A. Igarashi,
R. L. Potter,
and
G. R. Grotendorst.
Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10.
J. Cell Biol.
114:
1285-1294,
1991[Abstract].
30.
Buniatian, G.,
B. Hamprecht,
and
R. Gebhardt.
Glial fibrillary acidic protein as a marker of perisinusoidal stellate cells that can distinguish between the normal and myofibroblast-like phenotypes.
Biol. Cell
87:
65-73,
1996[Medline].
31.
Burns, A. R.,
S. I. Simon,
G. L. Kukielka,
J. L. Rowen,
H. Lu,
L. H. Mendoza,
E. S. Brown,
M. L. Entman,
and
C. W. Smith.
Chemotactic factors stimulate CD18-dependent canine neutrophil adherence and motility on lung fibroblasts.
J. Immunol.
156:
3389-3401,
1996[Abstract].
32.
Bussey, H.
Cell shape determination: a pivotal role for Rho.
Science
272:
224-225,
1996[Medline].
33.
Campbell, F.,
B. Hewlett,
J. Ho,
J. Huizinga,
and
R. H. Riddell.
Interstitial cells of Cajal (ICC) are absent or deranged in intestinal pseudo-obstruction (Abstract).
Lab. Invest.
78:
61A,
1998.
34.
Campbell, S. E.,
J. S. Janicki,
and
K. T. Weber.
Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone.
J. Mol. Cell. Cardiol.
27:
1545-1560,
1995[Medline].
35.
Campbell, S. E.,
and
L. C. Katwa.
Angiotensin II stimulated expression of transforming growth factor-1 in cardiac fibroblasts and myofibroblasts.
J. Mol. Cell. Cardiol.
29:
1947-1958,
1997[Medline].
36.
Casola, A.,
A. Kapoor,
J. I. Saada,
R. Mifflin,
D. W. Powell,
and
S. E. Crowe.
Chemokine expression by intestinal myofibroblasts (Abstract).
Gastroenterology
112:
A944,
1997.
37.
Chedid, M.,
J. S. Rubin,
K. G. Csaky,
and
S. A. Aaronson.
Regulation of keratinocyte growth factor gene expression by interleukin 1.
J. Biol. Chem.
269:
10753-10757,
1994
38.
Chinery, R.,
and
R. J. Coffey.
Trefoil peptides: less clandestine in the intestine.
Science
274:
204,
1996[Medline].
39.
Christopherson, K. S.,
and
D. S. Bredt.
Nitric oxide in excitable tissues: physiological roles and disease.
J. Clin. Invest.
100:
2424-2429,
1997
40.
Cintorino, M.,
E. Bellizzi de Marco,
P. Leoncini,
S. A. Tripodi,
L. J. Xu,
A. P. Sappino,
A. Schmitt-Graff,
and
G. Gabbiani.
Expression of -smooth-muscle actin in stromal cells of the uterine cervix during epithelial neoplastic changes.
Int. J. Cancer
47:
843-846,
1991[Medline].
41.
Clark, R. A.
Regulation of fibroplasia in cutaneous wound repair.
Am. J. Med. Sci.
306:
42-48,
1993[Medline].
42.
Clemmons, D. R.
Insulin-like growth factor binding proteins and their role in controlling IGF actions.
Cytokine Growth Factor Rev.
8:
45-62,
1997[Medline].
43.
Clemmons, D. R.
Role of insulin-like growth factor binding proteins in controlling IGF actions.
Mol. Cell. Endocrinol.
140:
19-24,
1998[Medline].
44.
Clemmons, D. R.,
W. Busby,
J. B. Clarke,
A. Parker,
C. Duan,
and
T. J. Nam.
Modifications of insulin-like growth factor binding proteins and their role in controlling IGF actions.
Endocr. J.
45, Suppl.:
S1-S8,
1998[Medline].
45.
Clouthier, D. E.,
S. A. Comerford,
and
R. E. Hammer.
Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-1 transgenic mice.
J. Clin. Invest.
100:
2697-2713,
1997
46.
Cockerill, G. W.,
O. Wiebkin,
R. Krishnan,
S. Huffam,
S. Graves,
J. R. Gamble,
and
M. A. Vadas.
Characterisation of a myofibroblast-like cell line from an angiosarcoma.
Int. J. Oncol.
9:
411-418,
1996.
47.
Cohn, S. M.,
S. Schloemann,
T. Tessner,
K. Seibert,
and
W. F. Stenson.
Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1.
J. Clin. Invest.
99:
1367-1379,
1997
48.
Crowston, J. G.,
M. Salmon,
P. T. Khaw,
and
A. N. Akbar.
T-lymphocyte-fibroblast interactions.
Biochem. Soc. Trans.
25:
529-531,
1997[Medline].
49.
Czernobilsky, B.,
E. Shezen,
B. Lifschitz-Mercer,
M. Fogel,
A. Luzon,
N. Jacob,
O. Skalli,
and
G. Gabbiani.
Alpha smooth muscle actin (alpha-SM actin) in normal human ovaries, in ovarian stromal hyperplasia and in ovarian neoplasms.
Virchows Arch. B Cell Pathol. Incl. Mol. Pathol.
57:
55-61,
1989[Medline].
50.
D'Amore, P. A.
Capillary growth: a two-cell system.
Semin. Cancer Biol.
3:
49-56,
1992[Medline].
51.
Darby, I.,
O. Skalli,
and
G. Gabbiani.
Alpha-smooth muscle actin is transiently expressed by myofibroblasts during experimental wound healing.
Lab. Invest.
63:
21-29,
1990[Medline].
52.
Der-Silaphet, T.,
J. Malysz,
S. Hagel,
A. L. Arsenault,
and
J. D. Huizinga.
Interstitial cells of Cajal direct normal propulsive contractile activity in the mouse small intestine.
Gastroenterology
114:
724-736,
1998[Medline].
53.
Desaki, J.,
T. Fujiwara,
and
T. Komuro.
A cellular reticulum of fibroblast-like cells in the rat intestine: scanning and transmission electron microscopy.
Arch. Histol. Jpn.
47:
179-186,
1984[Medline].
54.
Desmouliere, A.,
and
G. Gabbiani.
Myofibroblast differentiation during fibrosis.
Exp. Nephrol.
3:
134-139,
1995[Medline].
55.
Desmouliere, A.,
M. Redard,
I. Darby,
and
G. Gabbiani.
Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar.
Am. J. Pathol.
146:
56-66,
1995[Abstract].
56.
Desmouliere, A.,
L. Rubbia-Brandt,
A. Abdiu,
T. Walz,
A. Macieira-Coelho,
and
G. Gabbiani.
Alpha-smooth muscle actin is expressed in a subpopulation of cultured and cloned fibroblasts and is modulated by gamma-interferon.
Exp. Cell Res.
201:
64-73,
1992[Medline].
57.
Diehl, A. M.,
and
R. M. Rai.
Liver regeneration 3: regulation of signal transduction during liver regeneration.
FASEB J.
10:
215-227,
1996
58.
Dignass, A. U.,
and
D. K. Podolsky.
Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor .
Gastroenterology
105:
1323-1332,
1993[Medline].
59.
Dignass, A. U.,
S. Tsunekawa,
and
D. K. Podolsky.
Fibroblast growth factors modulate intestinal epithelial cell growth and migration.
Gastroenterology
106:
1254-1262,
1994[Medline].
60.
Dinarello, C. A.
Biologic basis for interleukin-1 in disease.
Blood
87:
2095-2147,
1996
61.
Doucet, C.,
D. Brouty-Boye,
C. Pottin-Clemenceau,
G. W. Canonica,
C. Jasmin,
and
B. Azzarone.
Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma.
J. Clin. Invest.
101:
2129-2139,
1998
62.
Enzan, H.,
H. Himeno,
S. Iwamura,
T. Saibara,
S. Onishi,
Y. Yamamoto,
E. Miyazaki,
and
H. Hara.
Sequential changes in human Ito cells and their relation to postnecrotic liver fibrosis in massive and submassive hepatic necrosis.
Virchows Arch.
426:
95-101,
1995[Medline].
63.
Espinoza, L. R.,
R. van Solingen,
M. L. Cuellar,
and
J. Angulo.
Insights into the pathogenesis of psoriasis and psoriatic arthritis.
Am. J. Med. Sci.
316:
271-276,
1998[Medline].
64.
Estevao-Costa, J.,
J. Correia-Pinto,
F. C. Rodrigues,
J. L. Carvalho,
M. Campos,
J. A. Dias,
F. Carneiro,
and
N. T. Santos.
Gastric inflammatory myofibroblastic proliferation in children.
Pediatr. Surg. Int.
13:
95-99,
1998[Medline].
65.
Eyden, B. P.
Brief review of the fibronexus and its significance for myofibroblastic differentiation and tumor diagnosis.
Ultrastruct. Pathol.
17:
611-622,
1993[Medline].
66.
Finch, P. W.,
V. Pricolo,
A. Wu,
and
S. D. Finkelstein.
Increased expression of keratinocyte growth factor messenger RNA associated with inflammatory bowel disease.
Gastroenterology
110:
441-451,
1996[Medline].
67.
Fiocchi, C.
Intestinal inflammation: a complex interplay of immune and nonimmune cell interactions.
Am. J. Physiol.
273 (Gastrointest. Liver Physiol. 36):
G769-G775,
1997
68.
Flaumenhaft, R.,
M. Abe,
P. Mignatti,
and
D. B. Rifkin.
Basic fibroblast growth factor-induced activation of latent transforming growth factor in endothelial cells: regulation of plasminogen activator activity.
J. Cell Biol.
118:
901-909,
1992[Abstract].
69.
Forstermann, U.,
J. P. Boissel,
and
H. Kleinert.
Expressional control of the "constitutive" isoforms of nitric oxide synthase (NOS I and NOS III).
FASEB J.
12:
773-790,
1998
70.
Frazier, K. S.,
and
G. R. Grotendorst.
Expression of connective tissue growth factor mRNA in the fibrous stroma of mammary tumors.
Int. J. Biochem. Cell Biol.
29:
153-161,
1997[Medline].
71.
Friedman, S. L.
The cellular basis of hepatic fibrosis.
N. Engl. J. Med.
328:
1828-1835,
1993
72.
Friedman, S. L.
Closing in on the signals of hepatic fibrosis.
Gastroenterology
112:
1406-1409,
1997[Medline].
73.
Fries, K. M.,
T. Blieden,
R. J. Looney,
G. D. Sempowski,
M. R. Silvera,
R. A. Willis,
and
R. P. Phipps.
Evidence of fibroblast heterogeneity and the role of fibroblast subpopulations in fibrosis.
Clin. Immunol. Immunopathol.
72:
283-292,
1994[Medline].
74.
Fritsch, C.,
P. Simon-Assmann,
M. Kedinger,
and
G. S. Evans.
Cytokines modulate fibroblast phenotype and epithelial-stroma interactions in rat intestine.
Gastroenterology
112:
826-838,
1997[Medline].
75.
Fuchs, E.,
and
D. W. Cleveland.
A structural scaffolding of intermediate filaments in health and disease.
Science
279:
514-519,
1998
76.
Fujimoto, J.,
M. Hori,
S. Ichigo,
and
T. Tamaya.
Ovarian steroids regulate the expression of basic fibroblast growth factor and its mRNA in fibroblasts derived from uterine endometrium.
Ann. Clin. Biochem.
34:
91-96,
1997[Medline].
77.
Furuya, K.,
S. Furuya,
and
S. Yamagishi.
Intracellular calcium responses and shape conversions induced by endothelin in cultured subepithelial fibroblasts of rat duodenal villi.
Pflügers Arch.
428:
97-104,
1994[Medline].
78.
Furuya, S.,
and
K. Furuya.
Characteristics of cultured subepithelial fibroblasts of rat duodenal villi.
Anat. Embryol.
187:
529-538,
1993[Medline].
79.
Furuya, S.,
R. Nagata,
Y. Ozaki,
K. Furuya,
T. Nakayama,
and
M. Nagahama.
A monoclonal antibody to astrocytes, subepithelial fibroblasts of small intestinal villi and interstitial cells of the myenteric plexus layer.
Anat. Embryol.
195:
113-126,
1997[Medline].
80.
Furuya, S.,
S. Naruse,
T. Nakayama,
and
K. Nokihara.
125I-endothelin binds to fibroblasts beneath the epithelium of rat small intestine.
J. Electron Microsc.
39:
264-268,
1990[Medline].
81.
Gabbiani, G.
The cellular derivation and the life span of the myofibroblast.
Pathol. Res. Pract.
192:
708-711,
1996[Medline].
82.
Gabbiani, G.,
and
E. Rungger-Brandle.
The fibroblast.
In: Handbook of Inflammation. Tissue Repair and Regeneration, edited by L. E. Glynn. Amsterdam: Elsevier/North-Holland Biomedical, 1981, p. 1-50.
83.
Gabbiani, G.,
G. B. Ryan,
and
G. Majne.
Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction.
Experientia
27:
549-550,
1971[Medline].
84.
Goke, M.,
M. Kanai,
and
D. K. Podolsky.
Intestinal fibroblasts regulate intestinal epithelial cell proliferation via hepatocyte growth factor.
Am. J. Physiol.
274 (Gastrointest. Liver Physiol. 37):
G809-G818,
1998
85.
Gorgas, K.,
and
P. Bock.
Myofibroblasts in the rat testicular capsule.
Cell Tissue Res.
154:
533-541,
1974[Medline].
86.
Graham, M. F.
Pathogenesis of intestinal strictures in Crohn's diseasean update.
Inflamm. Bowel Dis.
1:
220-227,
1995.
87.
Greenhalgh, D. G.,
K. H. Sprugel,
M. J. Murray,
and
R. Ross.
PDGF and FGF stimulate wound healing in the genetically diabetic mouse.
Am. J. Pathol.
136:
1235-1246,
1990[Abstract].
88.
Gressner, A. M.
Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis.
Kidney Int. Suppl.
54:
S39-S45,
1996[Medline].
89.
Grotendorst, G. R.
Connective tissue growth factor: a mediator of TGF- action on fibroblasts.
Cytokine Growth Factor Rev.
8:
171-179,
1997[Medline].
90.
Guido, M.,
M. Rugge,
L. Chemello,
G. Leandro,
G. Fattovich,
G. Giustina,
M. Cassaro,
and
A. Alberti.
Liver stellate cells in chronic viral hepatitis: the effect of interferon therapy.
J. Hepatol.
24:
301-307,
1996[Medline].
91.
Gulati, R.,
and
J. J. Peluso.
Opposing actions of hepatocyte growth factor and basic fibroblast growth factor on cell contact, intracellular free calcium levels, and rat ovarian surface epithelial cell viability.
Endocrinology
138:
1847-1856,
1997
92.
Gurbuz, A. K.,
F. M. Giardiello,
G. M. Petersen,
A. J. Krush,
G. J. Offerhaus,
S. V. Booker,
M. C. Kerr,
and
S. R. Hamilton.
Desmoid tumours in familial adenomatous polyposis.
Gut
35:
377-381,
1994[Abstract].
93.
Gurner, A.
The origin of Ia antigen-expressing cells in the rat kidney.
Am. J. Pathol.
127:
342-348,
1987[Abstract].
94.
Hall, A.
Rho GTPases and the actin cytoskeleton.
Science
279:
509-514,
1998
95.
Hall, P. A.,
P. J. Coates,
B. Ansari,
and
D. Hopwood.
Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis.
J. Cell Sci.
107:
3569-3577,
1994
96.
Hanauske-Abel, H. M.
Fibrosis: representative molecular elements, a basic concept, and emerging targets for suppressive treatment.
In: Hepatology: A Textbook of Liver Disease, edited by D. Zakim,
and T. D. Boyer. Philadelphia, PA: Saunders, 1996, p. 465-506.
97.
Hautmann, M. B.,
C. S. Madsen,
and
G. K. Owens.
A transforming growth factor (TGF
) control element drives TGF
-induced stimulation of smooth muscle
-actin gene expression in concert with two CArG elements.
J. Biol. Chem.
272:
10948-10956,
1997
98.
Hayward, S. W.,
M. A. Rosen,
and
G. R. Cunha.
Stromal-epithelial interactions in the normal and neoplastic prostate.
Br. J. Urol.
79, Suppl. 2:
18-26,
1997[Medline].
99.
Hebda, P. A.,
M. A. Collins,
and
M. D. Tharp.
Mast cell and myofibroblast in wound healing.
Dermatol. Clin.
11:
685-696,
1993[Medline].
100.
Hellerbrand, S.,
C. Wang,
H. Tsukamoto,
D. A. Brenner,
and
R. A. Rippe.
Expression of intracellular adhesion molecule 1 by activated hepatic stellate cells.
Hepatology
24:
670-676,
1996[Medline].
101.
Hernandez-Munoz, I.,
P. de la Torre,
J. A. Sanchez-Alcazar,
I. Garcia,
E. Santiago,
M. T. Munoz-Yague,
and
J. A. Solis-Herruzo.
Tumor necrosis factor inhibits collagen
1(I) gene expression in rat hepatic stellate cells through a G protein.
Gastroenterology
113:
625-640,
1997[Medline].
102.
Hinterleitner, T. A.,
J. I. Saada,
H. M. Berschneider,
D. W. Powell,
and
J. D. Valentich.
IL-1 stimulates intestinal myofibroblast COX gene expression and augments activation of Cl secretion in T84 cells.
Am. J. Physiol.
271 (Cell Physiol. 40):
C1262-C1268,
1996
103.
Hirota, S.,
K. Isozaki,
Y. Moriyama,
K. Hashimoto,
T. Nishida,
S. Ishiguro,
K. Kawano,
M. Hanada,
A. Kurata,
M. Takeda,
T. G. Muhammad,
Y. Matsuzawa,
Y. Kanakura,
Y. Shinomura,
and
Y. Kitamura.
Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.
Science
279:
577-580,
1998
104.
Hoeben, E.,
T. Briers,
H. Vanderstichele,
W. De Smet,
W. Heyns,
L. Deboel,
F. Vanderhoydonck,
and
G. Verhoeven.
Characterization of newly established testicular peritubular and prostatic stromal cell lines: potential use in the study of mesenchymal-epithelial interactions.
Endocrinology
136:
2862-2873,
1995[Abstract].
105.
Hogaboam, C. M.,
R. E. Smith,
and
S. L. Kunkel.
Dynamic interactions between lung fibroblasts and leukocytes: implications for fibrotic lung disease.
Proc. Assoc. Am. Physicians
110:
313-320,
1998[Medline].
106.
Holstein, A. F.,
M. Maekawa,
T. Nagano,
and
M. S. Davidoff.
Myofibroblasts in the lamina propria of human seminiferous tubules are dynamic structures of heterogeneous phenotype.
Arch. Histol. Cytol.
59:
109-125,
1996[Medline].
107.
Housley, R. M.,
C. F. Morris,
W. Boyle,
B. Ring,
R. Biltz,
J. E. Tarpley,
S. L. Aukerman,
P. L. Devine,
R. H. Whitehead,
and
G. F. Pierce.
Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract.
J. Clin. Invest.
94:
1764-1777,
1994[Medline].
108.
Hricik, D. E.,
M. Chung-Park,
and
J. R. Sedor.
Glomerulonephritis.
N. Engl. J. Med.
339:
888-899,
1998
109.
Huizinga, J. D.,
L. Thuneberg,
M. Kluppel,
J. Malysz,
H. B. Mikkelsen,
and
A. Bernstein.
W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity.
Nature
373:
347-349,
1995[Medline].
110.
Hull, M. A.,
D. J. Cullen,
N. Hudson,
and
C. J. Hawkey.
Basic fibroblast growth factor treatment for non-steroidal anti-inflammatory drug associated gastric ulceration.
Gut
37:
610-612,
1995[Abstract].
111.
Ichiki, Y.,
E. Smith,
E. C. LeRoy,
and
M. Trojanowska.
Different effects of basic fibroblast growth factor and transforming growth factor- on the two platelet-derived growth factor receptors' expression in scleroderma and healthy human dermal fibroblasts.
J. Invest. Dermatol.
104:
124-127,
1995[Abstract].
112.
Igarashi, A.,
H. Okochi,
D. M. Bradham,
and
G. R. Grotendorst.
Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.
Mol. Biol. Cell
4:
637-645,
1993[Abstract].
113.
Iredale, J. P.,
R. C. Benyon,
J. Pickering,
M. McCullen,
M. Northrop,
S. Pawley,
C. Hovell,
and
M. J. Arthur.
Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.
J. Clin. Invest.
102:
538-549,
1998
114.
Isaji, M.,
Y. Momose,
Y. Tatsuzawa,
and
J. Naito.
Modulation of morphology, proliferation and collagen synthesis in fibroblasts by the exudate from hypersensitive granulomatous inflammation in rats.
Int. Arch. Allergy Immunol.
104:
340-347,
1994[Medline].
115.
Isozaki, K.,
S. Hirota,
J. Miyagawa,
M. Taniguchi,
Y. Shinomura,
and
Y. Matsuzawa.
Deficiency of c-kit+ cells in patients with a myopathic form of chronic idiopathic intestinal pseudo-obstruction.
Am. J. Gastroenterol.
92:
332-334,
1997[Medline].
116.
Iwasaki, H.,
T. Isayama,
T. Ichiki,
and
M. Kikuchi.
Intermediate filaments of myofibroblasts. Immunochemical and immunocytochemical analyses.
Pathol. Res. Pract.
182:
248-254,
1987[Medline].
117.
Jain, M. K.,
M. D. Layne,
M. Watanabe,
M. T. Chin,
M. W. Feinberg,
N. E. Sibinga,
C. M. Hsieh,
S. F. Yet,
D. L. Stemple,
and
M. E. Lee.
In vitro system for differentiating pluripotent neural crest cells into smooth muscle cells.
J. Biol. Chem.
273:
5993-5996,
1998
118.
Jarnagin, W. R.,
D. C. Rockey,
V. E. Koteliansky,
S. S. Wang,
and
D. M. Bissell.
Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis.
J. Cell Biol.
127:
2037-2048,
1994[Abstract].
119.
Jobson, T. M.,
C. K. Billington,
and
I. P. Hall.
Regulation of proliferation of human colonic subepithelial myofibroblasts by mediators important in intestinal inflammation.
J. Clin. Invest.
101:
2650-2657,
1998
120.
Joyce, N. C.,
M. F. Haire,
and
G. E. Palade.
Morphologic and biochemical evidence for a contractile cell network within the rat intestinal mucosa.
Gastroenterology
92:
68-81,
1987[Medline].
121.
Kaiser, G. C.,
and
D. B. Polk.
Tumor necrosis factor regulates proliferation in a mouse intestinal cell line.
Gastroenterology
112:
1231-1240,
1997[Medline].
122.
Kaneda, K.,
W. Ekataksin,
M. Sogawa,
A. Matsumura,
A. Cho,
and
N. Kawada.
Endothelin-1-induced vasoconstriction causes a significant increase in portal pressure of rat liver: localized constrictive effect on the distal segment of preterminal portal venules as revealed by light and electron microscopy and serial reconstruction.
Hepatology
27:
735-747,
1998[Medline].
123.
Kapanci, Y.,
S. Burgan,
G. G. Pietra,
B. Conne,
and
G. Gabbiani.
Modulation of actin isoform expression in alveolar myofibroblasts (contractile interstitial cells) during pulmonary hypertension.
Am. J. Pathol.
136:
881-889,
1990[Abstract].
124.
Kasper, M.,
F. Golfert,
and
R. H. Funk.
Immunoelectron microscopical characterization of the epithelioid type of smooth muscle cells in human glomus organs.
Ultrastruct. Pathol.
21:
425-430,
1997[Medline].
125.
Kassen, A.,
D. M. Sutkowski,
H. Ahn,
J. A. Sensibar,
J. M. Kozlowski,
and
C. Lee.
Stromal cells of the human prostate: initial isolation and characterization.
Prostate
28:
89-97,
1996[Medline].
126.
Kaye, G. I.,
R. R. Pascal,
and
N. Lane.
The colonic pericryptal fibroblast sheath: replication, migration, and cytodifferentiation of a mesenchymal cell system in adult tissue. 3. Replication and differentiation in human hyperplastic and adenomatous polyps.
Gastroenterology
60:
515-536,
1971[Medline].
127.
Keane, M. P.,
D. A. Arenberg,
B. B. Moore,
C. L. Addison,
and
R. M. Strieter.
CXC chemokines and angiogenesis/angiostasis.
Proc. Assoc. Am. Physicians
110:
288-296,
1998[Medline].
128.
Keegan, A. D.,
J. J. Ryan,
and
W. E. Paul.
IL-4 regulates growth and differentiation by distinct mechanisms.
Immunologist
4:
194-198,
1996.
129.
Khulusi, S.,
A. M. Hanby,
J. M. Marrero,
P. Patel,
M. A. Mendall,
S. Badve,
R. Poulsom,
G. Elia,
N. A. Wright,
and
T. C. Northfield.
Expression of trefoil peptides pS2 and human spasmolytic polypeptide in gastric metaplasia at the margin of duodenal ulcers.
Gut
37:
205-209,
1995[Abstract].
130.
Kindon, H.,
C. Pothoulakis,
L. Thim,
K. Lynch-Devaney,
and
D. K. Podolsky.
Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein.
Gastroenterology
109:
516-523,
1995[Medline].
131.
Kinzler, K. W.,
and
B. Vogelstein.
Landscaping the cancer terrain.
Science
280:
1036-1037,
1998
132.
Klimpel, G. R.,
K. E. Langley,
J. Wypych,
J. S. Abrams,
A. K. Chopra,
and
D. W. Niesel.
A role for stem cell factor (SCF): c-kit interaction(s) in the intestinal tract response to Salmonella typhimurium infection.
J. Exp. Med.
184:
271-276,
1996[Abstract].
133.
Knittel, T.,
S. Aurisch,
K. Neubauer,
S. Eichhorst,
and
G. Ramadori.
Cell-type-specific expression of neural cell adhesion molecule (N-CAM) in Ito cells of rat liver. Up-regulation during in vitro activation and in hepatic tissue repair.
Am. J. Pathol.
149:
449-462,
1996[Abstract].
134.
Kohnen, G.,
S. Kertschanska,
R. Demir,
and
P. Kaufmann.
Placental villous stroma as a model system for myofibroblast differentiation.
Histochem. Cell Biol.
105:
415-429,
1996[Medline].
135.
Kolm-Litty, V.,
U. Sauer,
A. Nerlich,
R. Lehmann,
and
E. D. Schleicher.
High glucose-induced transforming growth factor 1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells.
J. Clin. Invest.
101:
160-169,
1998
136.
Komuro, T.
Re-evaluation of fibroblasts and fibroblast-like cells.
Anat. Embryol.
182:
103-112,
1990[Medline].
137.
Kothapalli, D.,
N. Hayashi,
and
G. R. Grotendorst.
Inhibition of TGF--stimulated CTGF gene expression and anchorage-independent growth by cAMP identifies a CTGF-dependent restriction point in the cell cycle.
FASEB J.
12:
1151-1161,
1998
138.
Kovacs, E. J.,
and
L. A. DiPietro.
Fibrogenic cytokines and connective tissue production.
FASEB J.
8:
854-861,
1994
139.
Kwon, B. S.,
S. Wang,
N. Udagawa,
V. Haridas,
Z. H. Lee,
K. K. Kim,
K. O. Oh,
J. Greene,
Y. Li,
J. Su,
R. Gentz,
B. B. Aggarwal,
and
J. Ni.
TR1, a new member of the tumor necrosis factor receptor superfamily, induces fibroblast proliferation and inhibits osteoclastogenesis and bone resorption.
FASEB J.
12:
845-854,
1998
140.
Lefebvre, O.,
M. P. Chenard,
R. Masson,
J. Linares,
A. Dierich,
M. LeMeur,
C. Wendling,
C. Tomasetto,
P. Chambon,
and
M. C. Rio.
Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein.
Science
274:
259-262,
1996
141.
Leveen, P.,
M. Pekny,
S. Gebre-Medhin,
B. Swolin,
E. Larsson,
and
C. Betsholtz.
Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities.
Genes Dev.
8:
1875-1887,
1994[Abstract].
142.
Lindahl, P.,
B. R. Johansson,
P. Leveen,
and
C. Betsholtz.
Pericyte loss and microaneurysm formation in PDGF-B-deficient mice.
Science
277:
242-245,
1997
143.
Liu, Q.,
X. X. Du,
D. T. Schindel,
Z. X. Yang,
F. J. Rescorla,
D. A. Williams,
and
J. L. Grosfeld.
Trophic effects of interleukin-11 in rats with experimental short bowel syndrome.
J. Pediatr. Surg.
31:
1047-1050,
1996[Medline].
144.
Lund, P. K.
Insulin-like growth factors.
In: Gut Peptides: Biochemistry and Physiology, edited by G. Dockray,
and J. H. Walsh. New York: Raven, 1994, p. 587-613.
145.
Lund, P. K.,
and
E. M. Zimmermann.
Insulin-like growth factors and inflammatory bowel disease.
In: Cytokines and Growth Factors in Gastroenterology, edited by R. Goodlad,
and N. Wright. London: Ballière, Tindal, & Cox, 1996, p. 83-96.
146.
Macdonald, T. T.,
and
S. L. Pender.
Proteolytic enzymes in inflammatory bowel disease.
Inflamm. Bowel Dis.
4:
157-164,
1998[Medline].
147.
Mallat, A.,
C. Gallois,
J. Tao,
A. Habib,
J. Maclouf,
P. Mavier,
A. M. Preaux,
and
S. Lotersztajn.
Platelet-derived growth factor-BB and thrombin generate positive and negative signals for human hepatic stellate cell proliferation. Role of a prostaglandin/cyclic AMP pathway and cross-talk with endothelin receptors.
J. Biol. Chem.
273:
27300-27305,
1998
148.
Mallat, A.,
A. M. Preaux,
C. Serradeil-Le Gal,
D. Raufaste,
C. Gallois,
D. A. Brenner,
C. Bradham,
J. Maclouf,
V. Iourgenko,
L. Fouassier,
D. Dhumeaux,
P. Mavier,
and
S. Lotersztajn.
Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors.
J. Clin. Invest.
98:
2771-2778,
1996
149.
Markowitz, S. D.
Atherosclerosis, just another cancer?
J. Clin. Invest.
100:
2143-2145,
1997
150.
Marra, F.,
A. Gentilini,
M. Pinzani,
G. G. Choudhury,
M. Parola,
H. Herbst,
M. U. Dianzani,
G. Laffi,
H. E. Abboud,
and
P. Gentilini.
Phosphatidylinositol 3-kinase is required for platelet-derived growth factor's actions on hepatic stellate cells.
Gastroenterology
112:
1297-1306,
1997[Medline].
151.
Marra, F.,
G. Grandaliano,
A. J. Valente,
and
H. E. Abboud.
Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury.
Hepatology
22:
780-787,
1995[Medline].
152.
Marsh, M. N.,
and
J. S. Trier.
Morphology and cell proliferation of subepithelial fibroblasts in adult mouse jejunum. II. Radioautographic studies.
Gastroenterology
67:
636-645,
1974[Medline].
153.
Martin, M.,
P. Pujuguet,
and
F. Martin.
Role of stromal myofibroblasts infiltrating colon cancer in tumor invasion.
Pathol. Res. Pract.
192:
712-717,
1996[Medline].
154.
Martinez-Hernandez, A.,
and
P. S. Amenta.
The extracellular matrix in hepatic regeneration.
FASEB J.
9:
1401-1410,
1995
155.
Masur, S. K.,
H. S. Dewal,
T. T. Dinh,
I. Erenburg,
and
S. Petridou.
Myofibroblasts differentiate from fibroblasts when plated at low density.
Proc. Natl. Acad. Sci. USA
93:
4219-4223,
1996
156.
Mattey, D. L.
Interleukin-4 induces myofibroblast differentiation in synovial fibroblasts.
Biochem. Soc. Trans.
25:
290S,
1997[Medline].
157.
Mayer-Proschel, M.,
M. S. Rao,
and
M. Noble.
Progenitor cells of the central nervous system: a boon for clinical neuroscience.
J. NIH Res.
9:
31-36,
1997.
158.
McCafferty, D. M.,
J. S. Mudgett,
M. G. Swain,
and
P. Kubes.
Inducible nitric oxide synthase plays a critical role in resolving intestinal inflammation.
Gastroenterology
112:
1022-1027,
1997[Medline].
159.
McCaffrey, T. A.,
B. Du,
S. Consigli,
P. Szabo,
P. J. Bray,
L. Hartner,
B. B. Weksler,
T. A. Sanborn,
G. Bergman,
and
H. L. J. Bush.
Genomic instability in the type II TGF-1 receptor gene in atherosclerotic and restenotic vascular cells.
J. Clin. Invest.
100:
2182-2188,
1997
160.
Mené, P.,
M. S. Simonson,
and
M. J. Dunn.
Eicosanoids, mesangial contraction, and intracellular signal transduction.
Tohoku J. Exp. Med.
166:
57-73,
1992[Medline].
161.
Mermall, V.,
P. L. Post,
and
M. S. Mooseker.
Unconventional myosins in cell movement, membrane traffic, and signal transduction.
Science
279:
527-533,
1998
162.
Miller, S. M.,
G. Farrugia,
P. F. Schmalz,
L. G. Ermilov,
M. D. Maines,
and
J. H. Szurszewski.
Heme oxygenase 2 is present in interstitial cell networks of the mouse small intestine.
Gastroenterology
114:
239-244,
1998[Medline].
163.
Moore, R.,
S. Carlson,
and
J. L. Madara.
Villus contraction aids repair of intestinal epithelium after injury.
Am. J. Physiol.
257 (Gastrointest. Liver Physiol. 20):
G274-G283,
1989
164.
Mori, N.,
Y. Doi,
K. Hara,
M. Yoshizuka,
K. Ohsato,
and
S. Fujimoto.
Role of multipotent fibroblasts in the healing colonic mucosa of rabbits. Ultrastructural and immunocytochemical study.
Histol. Histopathol.
7:
583-590,
1992[Medline].
165.
Muchaneta-Kubara, E. C.,
and
A. M. el Nahas.
Myofibroblast phenotypes expression in experimental renal scarring.
Nephrol. Dial. Transplant.
12:
904-915,
1997[Abstract].
166.
Mucke, L.,
and
M. Eddleston.
Astrocytes in infectious and immune-mediated diseases of the central nervous system.
FASEB J.
7:
1226-1232,
1993
167.
Muhl, H.,
and
J. Pfeilschifter.
Amplification of nitric oxide synthase expression by nitric oxide in interleukin 1-stimulated rat mesangial cells.
J. Clin. Invest.
95:
1941-1946,
1995[Medline].
168.
Musso, O.,
M. Rehn,
J. Saarela,
N. Theret,
J. Lietard,
Hintikka,
D. Lotrian,
J. P. Campion,
T. Pihlajaniemi,
and
B. Clement.
Collagen XVIII is localized in sinusoids and basement membrane zones and expressed by hepatocytes and activated stellate cells in fibrotic human liver.
Hepatology
28:
98-107,
1998[Medline].
169.
Nakamura, M.,
and
H. Ishii.
Myofibroblasts and ECL cells are altered in the aged rat stomach (Abstract).
Gastroenterology
114:
A240,
1998.
170.
Nakamura, M.,
M. Oda,
Y. Nishizaki,
K. Kaneko,
T. Azuma,
and
M. Tsuchiya.
Fluorescent histochemical study on the localization of myofibroblasts in the healing of acetic acid-induced gastric ulcers in the rat.
Scand. J. Gastroenterol. Suppl.
162:
150-153,
1989[Medline].
171.
Ng, Y. Y.,
T. P. Huang,
W. C. Yang,
Z. P. Chen,
A. H. Yang,
W. Mu,
D. J. Nikolic-Paterson,
R. C. Atkins,
and
H. Y. Lan.
Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats.
Kidney Int.
54:
864-876,
1998[Medline].
172.
Novotny, G. E.,
and
H. Pau.
Myofibroblast-like cells in human anterior capsular cataract.
Virchows Arch. A Pathol. Anat. Histopathol.
404:
393-401,
1984[Medline].
173.
Nusrat, A.,
C. A. Parkos,
A. E. Bacarra,
P. J. Godowski,
C. Delp-Archer,
E. M. Rosen,
and
J. L. Madara.
Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium.
J. Clin. Invest.
93:
2056-2065,
1994[Medline].
174.
Ogawa, M.,
Y. Matsuzaki,
S. Nishikawa,
S. Hayashi,
T. Kunisada,
T. Sudo,
T. Kina,
and
H. Nakauchi.
Expression and function of c-kit in hemopoietic progenitor cells.
J. Exp. Med.
174:
63-71,
1991[Abstract].
175.
Orazi, A.,
X. Du,
Z. Yang,
M. Kashai,
and
D. A. Williams.
Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation.
Lab. Invest.
75:
33-42,
1996[Medline].
176.
Pache, J. C.,
P. G. Christakos,
D. E. Gannon,
J. J. Mitchell,
R. B. Low,
and
K. O. Leslie.
Myofibroblasts in diffuse alveolar damage of the lung.
Mod. Pathol.
11:
1064-1070,
1998[Medline].
177.
Palmer, B. F.
The renal tubule in the progression of chronic renal failure.
J. Investig. Med.
45:
346-361,
1997[Medline].
178.
Pang, G.,
L. Couch,
R. Batey,
R. Clancy,
and
A. Cripps.
GM-CSF, IL-1, IL-1
, IL-6, IL-8, IL-10, ICAM-1 and VCAM-1 gene expression and cytokine production in human duodenal fibroblasts stimulated with lipopolysaccharide, IL-1
and TNF
.
Clin. Exp. Immunol.
96:
437-443,
1994[Medline].
179.
Papanicolaou, D. A.,
R. L. Wilder,
S. C. Manolagas,
and
G. P. Chrousos.
The pathophysiologic roles of interleukin-6 in human disease.
Ann. Intern. Med.
128:
127-137,
1998
180.
Pascal, R. R.,
G. I. Kaye,
and
N. Lane.
Colonic pericryptal fibroblast sheath: replication, migration, and cytodifferentiation of a mesenchymal cell system in adult tissue. I. Autoradiographic studies of normal rabbit colon.
Gastroenterology
54:
835-851,
1968[Medline].
181.
Peehl, D. M.,
and
R. G. Sellers.
Induction of smooth muscle cell phenotype in cultured human prostatic stromal cells.
Exp. Cell Res.
232:
208-215,
1997[Medline].
182.
Peled, A.,
D. Zipori,
O. Abramsky,
H. Ovadia,
and
E. Shezen.
Expression of -smooth muscle actin in murine bone marrow stromal cells.
Blood
78:
304-309,
1991[Abstract].
183.
Pelet, A.,
O. Geneste,
P. Edery,
A. Pasini,
S. Chappuis,
T. Atti,
A. Munnich,
G. Lenoir,
S. Lyonnet,
and
M. Billaud.
Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease.
J. Clin. Invest.
101:
1415-1423,
1998
184.
Petridou, S.,
and
S. K. Masur.
Immunodetection of connexins and cadherins in corneal fibroblasts and myofibroblasts.
Invest. Ophthalmol. Vis. Sci.
37:
1740-1748,
1996[Abstract].
185.
Pfeilschifter, J.
Mesangial cells orchestrate inflammation in the renal glomerulus.
News Physiol. Sci.
9:
271-276,
1994.
186.
Plaut, A. G.
Trefoil peptides in the defense of the gastrointestinal tract.
N. Engl. J. Med.
336:
506-507,
1997
187.
Playford, R. J.
Peptides and gastrointestinal mucosal integrity.
Gut
37:
595-597,
1995[Medline].
188.
Playford, R. J.,
and
N. A. Wright.
Why is epidermal growth factor present in the gut lumen?
Gut
38:
303-305,
1996[Abstract].
189.
Podolsky, D. K.
Healing the epithelium: solving the problem from two sides.
J. Gastroenterol.
32:
122-126,
1997[Medline].
190.
Polk, D. B.
Epidermal growth factor receptor-stimulated intestinal epithelial cell migration requires phospholipase C activity.
Gastroenterology
114:
493-502,
1998[Medline].
191.
Powell, D. W., R. C. Mifflin, J. D. Valentich, S. E. Crowe, J. I. Saada, and A. B. West. Myofibroblasts. II. Intestinal subepithelial
myofibroblasts. Am. J. Physiol. 277 (Cell
Physiol. 46). In press.
192.
Racine-Samson, L.,
D. C. Rockey,
and
D. M. Bissell.
The role of alpha1beta1 integrin in wound contraction. A quantitative analysis of liver myofibroblasts in vivo and in primary culture.
J. Biol. Chem.
272:
30911-30917,
1997
193.
Ramakers, G. J. A.,
and
W. H. Moolenaar.
Regulation of astrocyte morphology by RhoA and lysophosphatidic acid.
Exp. Cell Res.
245:
252-262,
1998[Medline].
194.
Ray, P.,
W. Tang,
P. Wang,
R. Homer,
C. Kuhn,
R. A. Flavell,
and
J. A. Elias.
Regulated overexpression of interleukin 11 in the lung. Use to dissociate development-dependent and -independent phenotypes.
J. Clin. Invest.
100:
2501-2511,
1997
195.
Reddy, L.,
H. S. Wang,
C. R. Keese,
I. Giaever,
and
T. J. Smith.
Assessment of rapid morphological changes associated with elevated cAMP levels in human orbital fibroblasts.
Exp. Cell Res.
245:
360-367,
1998[Medline].
196.
Reinecker, H. C.,
R. P. MacDermott,
S. Mirau,
A. Dignass,
and
D. K. Podolsky.
Intestinal epithelial cells both express and respond to interleukin 15.
Gastroenterology
111:
1706-1713,
1996[Medline].
197.
Reitamo, S.,
A. Remitz,
K. Tamai,
and
J. Uitto.
Interleukin-10 modulates type I collagen and matrix metalloprotease gene expression in cultured human skin fibroblasts.
J. Clin. Invest.
6:
2489-2492,
1994.
198.
Remuzzi, G.,
and
T. Bertani.
Pathophysiology of progressive nephropathies.
N. Engl. J. Med.
339:
1448-1456,
1998
199.
Richman, P. I.,
R. Tilly,
J. R. Jass,
and
W. F. Bodmer.
Colonic pericrypt sheath cells: characterisation of cell type with new monoclonal antibody.
J. Clin. Pathol.
40:
593-600,
1987[Abstract].
200.
Riegler, M.,
R. Sedivy,
T. Sogukoglu,
E. Cosentini,
G. Bischof,
B. Teleky,
W. Feil,
R. Schiessel,
G. Hamilton,
and
E. Wenzl.
Epidermal growth factor promotes rapid response to epithelial injury in rabbit duodenum in vitro.
Gastroenterology
111:
28-36,
1996[Medline].
201.
Roberts, A. I.,
S. C. Nadler,
and
E. C. Ebert.
Mesenchymal cells stimulate human intestinal intraepithelial lymphocytes.
Gastroenterology
113:
144-150,
1997[Medline].
202.
Rockey, D. C.,
and
J. J. Chung.
Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility.
J. Clin. Invest.
95:
1199-1206,
1995[Medline].
203.
Ronnov-Jessen, L.,
and
O. W. Petersen.
Induction of -smooth muscle actin by transforming growth factor-
1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia.
Lab. Invest.
68:
696-707,
1993[Medline].
204.
Ronnov-Jessen, L.,
O. W. Petersen,
V. E. Koteliansky,
and
M. J. Bissell.
The origin of the myofibroblasts in breast cancer: recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells.
J. Clin. Invest.
95:
859-873,
1995[Medline].
205.
Rosenbaum, J.,
S. Blazejewski,
A. M. Preaux,
A. Mallat,
D. Dhumeaux,
and
P. Mavier.
Fibroblast growth factor 2 and transforming growth factor 1 interactions in human liver myofibroblasts.
Gastroenterology
109:
1986-1996,
1995[Medline].
206.
Rubbia-Brandt, L.,
G. Mentha,
A. Desmouliere,
A. M. Alto Costa,
E. Giostra,
G. Molas,
H. Enzan,
and
G. Gabbiani.
Hepatic stellate cells reversibly express -smooth muscle actin during acute hepatic ischemia.
Transplant. Proc.
29:
2390-2395,
1997[Medline].
207.
Rubin, J. S.,
D. P. Bottaro,
M. Chedid,
T. Miki,
D. Ron,
G. Cheon,
W. G. Taylor,
E. Fortney,
H. Sakata,
and
P. W. Finch.
Keratinocyte growth factor.
Cell Biol. Int.
19:
399-411,
1995[Medline].
208.
Rungger-Brandle, E.,
and
G. Gabbiani.
The role of cytoskeletal and cytocontractile elements in pathologic processes.
Top. Clin. Nurs.
8:
361-392,
1986.
209.
Ryu, J. H.,
T. V. Colby,
and
T. E. Hartman.
Idiopathic pulmonary fibrosis: current concepts.
Mayo Clin. Proc.
73:
1085-1101,
1998[Medline].
210.
Saada, J. I.,
R. Mifflin,
and
D. W. Powell.
Nonsteroidal anti-inflammatory drugs (NSAIDs) induce cyclooxygenase-2 (COX-2) expression via delayed activation of ERK and P38 MAPK pathways in human intestinal subepithelial myofibroblasts synergistic interaction with interleukin-1 induced signaling (Abstract).
Gastroenterology
116:
A297,
1999.
211.
Salmon-Ehr, V.,
H. Serpier,
B. Nawrocki,
P. Gillery,
C. Clavel,
B. Kalis,
P. Birembaut,
and
F. X. Maquart.
Expression of interleukin-4 in scleroderma skin specimens and scleroderma fibroblast cultures. Potential role in fibrosis.
Arch. Dermatol.
132:
802-806,
1996[Abstract].
212.
Sanders, K. M.
A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract.
Gastroenterology
111:
492-515,
1996[Medline].
213.
Sappino, A. P.,
I. Masouye,
J. H. Saurat,
and
G. Gabbiani.
Smooth muscle differentiation in scleroderma fibroblastic cells.
Am. J. Pathol.
137:
585-591,
1990[Abstract].
214.
Sappino, A. P.,
W. Schurch,
and
G. Gabbiani.
Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations.
Lab. Invest.
63:
144-161,
1990[Medline].
215.
Saunders, K. B.,
and
P. A. D'Amore.
An in vitro model for cell-cell interactions.
In Vitro Cell. Dev. Biol.
28A:
521-528,
1992.
216.
Schmitt-Graff, A.,
A. Desmouliere,
and
G. Gabbiani.
Heterogeneity of myofibroblast phenotypic features: an example of fibroblastic cell plasticity.
Virchows Arch.
425:
3-24,
1994[Medline].
217.
Schmitt-Graff, A.,
H. Pau,
R. Spahr,
H. M. Piper,
O. Skalli,
and
G. Gabbiani.
Appearance of -smooth muscle actin in human eye lens cells of anterior capsular cataract and in cultured bovine lens-forming cells.
Differentiation
43:
115-122,
1990[Medline].
218.
Schmitt-Graff, A.,
O. Skalli,
and
G. Gabbiani.
Alpha-smooth muscle actin is expressed in a subset of bone marrow stromal cells in normal and pathological conditions.
Virchows Arch. B Cell Pathol. Incl. Mol. Pathol.
57:
291-302,
1989[Medline].
219.
Schuppan, D.,
M. Schmid,
R. Somasundaram,
R. Ackermann,
M. Ruehl,
T. Nakamura,
and
E. O. Riecken.
Collagens in the liver extracellular matrix bind hepatocyte growth factor.
Gastroenterology
114:
139-152,
1998[Medline].
220.
Scott-Burden, T.
Extracellular matrix: the cellular environment.
News Physiol. Sci.
9:
110-115,
1994.
221.
Sempowski, G. D.,
J. Rozenblit,
T. J. Smith,
and
R. P. Phipps.
Human orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine production.
Am. J. Physiol.
274 (Cell Physiol. 43):
C707-C714,
1998
222.
Serini, G.,
M. L. Bochaton-Piallat,
P. Ropraz,
A. Geinoz,
L. Borsi,
L. Zardi,
and
G. Gabbiani.
The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-1.
J. Cell Biol.
142:
873-881,
1998
223.
Shi, Y.,
J. E. O'Brien, Jr.,
A. Fard,
and
A. Zalewski.
Transforming growth factor-1 expression and myofibroblast formation during arterial repair.
Arterioscler. Thromb. Vasc. Biol.
16:
1298-1305,
1996
224.
Shum, D. T.,
and
R. M. McFarlane.
Histogenesis of Dupuytren's disease: an immunohistochemical study of 30 cases.
J. Hand Surg. [Am.]
13:
61-67,
1988[Medline].
225.
Silen, W.,
and
S. Ito.
Mechanisms for rapid re-epithelialization of the gastric mucosal surface.
Annu. Rev. Physiol.
47:
217-229,
1985[Medline].
226.
Simmons, J. G.,
J. B. Pucilowska,
and
P. K. Lund.
Autocrine and paracrine actions of intestinal fibroblast-derived insulin-like growth factors.
Am. J. Physiol.
276 (Gastrointest. Liver Physiol. 39):
G817-G827,
1999
227.
Simon-Assmann, P.,
M. Kedinger,
A. De Arcangelis,
V. Rousseau,
and
P. Simo.
Extracellular matrix components in intestinal development.
Experientia
51:
883-900,
1995[Medline].
228.
Singer, I. I.
The fibronexus: a transmembrane association of fibronectin-containing fibers and bundles of 5 nm microfilaments in hamster and human fibroblasts.
Cell
16:
675-685,
1979[Medline].
229.
Singer, I. I.
Fibronexus formation is an early event during fibronectin-induced restoration of more normal morphology and substrate adhesion patterns in transformed hamster fibroblasts.
J. Cell Sci.
56:
1-20,
1982[Abstract].
230.
Singer, I. I.,
D. M. Kazazis,
and
D. W. Kawka.
Localization of the fibronexus at the surface of granulation tissue myofibroblasts using double-label immunogold electron microscopy on ultrathin frozen sections.
Eur. J. Cell Biol.
38:
94-101,
1985[Medline].
231.
Singer, I. I.,
D. M. Kazazis,
D. W. Kawka,
E. A. Rupp,
and
E. K. Bayne.
Extracellular matrix-cytoskeletal interactions in rheumatoid arthritis. I. Immunoelectron microscopic analysis of the fibronexus at the adhesive surface of normal porcine type B synoviocytes in vitro.
Arthritis Rheum.
28:
1105-1116,
1985[Medline].
232.
Singer, I. I.,
and
P. R. Paradiso.
A transmembrane relationship between fibronectin and vinculin (130 kd protein): serum modulation in normal and transformed hamster fibroblasts.
Cell
24:
481-492,
1981[Medline].
233.
Smits, R.,
W. van der Houven van Oordt,
A. Luz,
C. Zurcher,
S. Jagmohan-Changur,
C. Breukel,
P. M. Khan,
and
R. Fodde.
Apc1638N: a mouse model for familial adenomatous polyposis-associated desmoid tumors and cutaneous cysts.
Gastroenterology
114:
275-283,
1998[Medline].
234.
Soriano, P.
Abnormal kidney development and hematological disorders in PDGF -receptor mutant mice.
Genes Dev.
8:
1888-1896,
1994[Abstract].
235.
Sprenger, H.,
A. Kaufmann,
H. Garn,
B. Lahme,
D. Gemsa,
and
A. M. Gressner.
Induction of neutrophil-attracting chemokines in transforming rat hepatic stellate cells.
Gastroenterology
113:
277-285,
1997[Medline].
236.
Strong, S. A.,
T. T. Pizarro,
J. S. Klein,
F. Cominelli,
and
C. Fiocchi.
Proinflammatory cytokines differentially modulate their own expression in human intestinal mucosal mesenchymal cells.
Gastroenterology
114:
1244-1256,
1998[Medline].
237.
Synnerstad, I.,
E. Ekblad,
F. Sundler,
and
L. Holm.
Gastric mucosal smooth muscles may explain oscillations in glandular pressure: role of vasoactive intestinal peptide.
Gastroenterology
114:
284-294,
1998[Medline].
238.
Tamm, E. R.,
A. Siegner,
A. Baur,
and
E. Lutjen-Drecoll.
Transforming growth factor-1 induces
-smooth muscle-actin expression in cultured human and monkey trabecular meshwork.
Exp. Eye Res.
62:
389-397,
1996[Medline].
239.
Tang, W. W.,
T. R. Ulich,
D. L. Lacey,
D. C. Hill,
M. Qi,
S. A. Kaufman,
G. Y. Van,
J. E. Tarpley,
and
J. S. Yee.
Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis.
Am. J. Pathol.
148:
1169-1180,
1996[Abstract].
240.
Tetsuka, T.,
L. D. Baier,
and
A. R. Morrison.
Antioxidants inhibit interleukin-1-induced cyclooxygenase and nitric-oxide synthase expression in rat mesangial cells. Evidence for post-transcriptional regulation.
J. Biol. Chem.
271:
11689-11693,
1996
241.
Tetsuka, T.,
D. Daphna-Iken,
S. K. Srivastava,
L. D. Baier,
J. DuMaine,
and
A. R. Morrison.
Cross-talk between cyclooxygenase and nitric oxide pathways: prostaglandin E2 negatively modulates induction of nitric oxide synthase by interleukin 1.
Proc. Natl. Acad. Sci. USA
91:
12168-12172,
1994
242.
Tomasek, J. J.,
C. J. Haaksma,
R. J. Eddy,
and
M. B. Vaughan.
Fibroblast contraction occurs on release of tension in attached collagen lattices: dependency on an organized actin cytoskeleton and serum.
Anat. Rec.
232:
359-368,
1992[Medline].
243.
Torihashi, S.,
W. T. Gerthoffer,
S. Kobayashi,
and
K. M. Sanders.
Identification and classification of interstitial cells in the canine proximal colon by ultrastructure and immunocytochemistry.
Histochemistry
101:
169-183,
1994[Medline].
244.
Torihashi, S.,
S. M. Ward,
and
K. M. Sanders.
Development of c-Kit-positive cells and the onset of electrical rhythmicity in murine small intestine.
Gastroenterology
112:
144-155,
1997[Medline].
245.
Uribe, J. M.,
and
K. E. Barrett.
Nonmitogenic actions of growth factors: an integrated view of their role in intestinal physiology and pathophysiology.
Gastroenterology
112:
255-268,
1997[Medline].
246.
Valentich, J. D.,
V. Popov,
J. I. Saada,
and
D. W. Powell.
Phenotypic characterization of an intestinal subepithelial myofibroblast cell line.
Am. J. Physiol.
272 (Cell Physiol. 41):
C1513-C1524,
1997
247.
Valentich, J. D.,
and
D. W. Powell.
Intestinal subepithelial myofibroblasts and mucosal immunophysiology.
Curr. Opin. Gastroenterol.
10:
645-651,
1994.
248.
Vanderwinden, J. M.,
H. Liu,
M. H. De Laet,
and
J. J. Vanderhaeghen.
Study of the interstitial cells of Cajal in infantile hypertrophic pyloric stenosis.
Gastroenterology
111:
279-288,
1996[Medline].
249.
Vanderwinden, J. M.,
J. J. Rumessen,
H. Liu,
D. Descamps,
M. H. De Laet,
and
J. J. Vanderhaeghen.
Interstitial cells of Cajal in human colon and in Hirschsprung's disease.
Gastroenterology
111:
901-910,
1996[Medline].
250.
Villaschi, S.,
and
R. F. Nicosia.
Paracrine interactions between fibroblasts and endothelial cells in a serum-free coculture model. Modulation of angiogenesis and collagen gel contraction.
Lab. Invest.
71:
291-299,
1994[Medline].
251.
Vyas, S. K.,
H. Leyland,
J. Gentry,
and
M. J. Arthur.
Rat hepatic lipocytes synthesize and secrete transin (stromelysin) in early primary culture.
Gastroenterology
109:
889-898,
1995[Medline].
252.
Wallace, J. L.,
and
D. N. Granger.
The cellular and molecular basis of gastric mucosal defense.
FASEB J.
10:
731-740,
1996
253.
Walshe, R.,
P. Esser,
P. Wiedemann,
and
K. Heimann.
Proliferative retinal diseases: myofibroblasts cause chronic vitreoretinal traction.
Br. J. Ophthalmol.
76:
550-552,
1992[Abstract].
254.
Wang, H.,
C. R. Keese,
I. Giaever,
and
T. J. Smith.
Prostaglandin E2 alters human orbital fibroblast shape through a mechanism involving the generation of cyclic adenosine monophosphate.
J. Clin. Endocrinol. Metab.
80:
3553-3560,
1995[Abstract].
255.
Wang, J.,
W. Niu,
Y. Nikiforov,
S. Naito,
S. Chernausek,
D. Witte,
D. LeRoith,
A. Strauch,
and
J. A. Fagin.
Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic mice.
J. Clin. Invest.
100:
1425-1439,
1997
256.
Wang, Q. P.,
E. Escudier,
F. Roudot-Thoraval,
I. Abd-Al Samad,
R. Peynegre,
and
A. Coste.
Myofibroblast accumulation induced by transforming growth factor- is involved in the pathogenesis of nasal polyps.
Laryngoscope
107:
926-931,
1997[Medline].
257.
Ward, S. M.,
A. J. Burns,
S. Torihashi,
S. C. Harney,
and
K. M. Sanders.
Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants.
Am. J. Physiol.
269 (Cell Physiol. 38):
C1577-C1585,
1995
258.
Weber, K. T.,
Y. Sun,
and
L. C. Katwa.
Myofibroblasts and local angiotensin II in rat cardiac tissue repair.
Int. J. Biochem. Cell Biol.
29:
31-42,
1997[Medline].
259.
Wilborn, J.,
L. J. Crofford,
M. D. Burdick,
S. L. Kunkel,
R. M. Strieter,
and
M. Peters-Golden.
Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2.
J. Clin. Invest.
95:
1861-1868,
1995[Medline].
260.
Wright, N. A.,
C. Pike,
and
G. Elia.
Induction of a novel epidermal growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells.
Nature
343:
82-85,
1990[Medline].
261.
Xing, Z.,
J. Gauldie,
G. Cox,
H. Baumann,
M. Jordana,
X. F. Lei,
and
M. K. Achong.
IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses.
J. Clin. Invest.
101:
311-320,
1998
262.
Yamagishi, S.,
K. Kobayashi,
and
H. Yamamoto.
Vascular pericytes not only regulate growth, but also preserve prostacyclin-producing ability and protect against lipid peroxide-induced injury of co-cultured endothelial cells.
Biochem. Biophys. Res. Commun.
190:
418-425,
1993[Medline].
263.
Yamakage, A.,
K. Kikuchi,
E. A. Smith,
E. C. LeRoy,
and
M. Trojanowska.
Selective upregulation of platelet-derived growth factor receptors by transforming growth factor
in scleroderma fibroblasts.
J. Exp. Med.
175:
1227-1234,
1992[Abstract].
264.
Yashiro, M.,
Y. S. Chung,
T. Kubo,
F. Hato,
and
M. Sowa.
Differential responses of scirrhous and well-differentiated gastric cancer cells to orthotopic fibroblasts.
Br. J. Cancer
74:
1096-1103,
1996[Medline].
265.
Yee, H. F., Jr.
Rho directs activation-associated changes in rat hepatic stellate cell morphology via regulation of the actin cytoskeleton.
Hepatology
28:
843-850,
1998[Medline].
266.
Yoshioka, H.,
G. Ohshio,
M. Inada,
Y. Hamashima,
and
T. Miyake.
Immunohistochemical localization of the actin in the healing stage of gastric ulcers.
J. Exp. Pathol.
3:
271-280,
1987[Medline].
267.
Youngman, K. R.,
P. L. Simon,
G. A. West,
F. Cominelli,
D. Rachmilewitz,
J. S. Klein,
and
C. Fiocchi.
Localization of intestinal interleukin 1 activity and protein and gene expression to lamina propria cells.
Gastroenterology
104:
749-758,
1993[Medline].
268.
Zimmermann, E. M.
Intestinal fibrosis in inflammatory bowel disease.
Regul. Pept. Lett.
VII:
60-63,
1997.
269.
Zimmermann, E. M.,
L. Li,
Y. T. Hou,
M. Cannon,
G. M. Christman,
and
K. N. Bitar.
IGF-I induces collagen and IGFBP-5 mRNA in rat intestinal smooth muscle.
Am. J. Physiol.
273 (Gastrointest. Liver Physiol. 36):
G875-G882,
1997