Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Hepatic stellate cell activation is a complex process. Paradoxes and controversies include the origin(s) of hepatic stellate cells, the regulation of membrane receptor signaling and transcription, and the fate of the cells once liver injury resolves. Major themes have emerged, including the dominance of autocrine signaling and the identification of counterregulatory stimuli that oppose key features of activated cells. Advances in analytical methods including proteomics and gene array, coupled with powerful bioinformatics, promise to revolutionize how we view cellular responses. Our understanding of stellate cell activation is likely to benefit from these advances, unearthing modes of regulating cellular behavior that are not even conceivable on the basis of current paradigms.
signaling; transcription; extracellular matrix; receptors; hepatic fibrosis
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
ACTIVATED HEPATIC STELLATE cells (HSCs) have been established as the unequivocal source of extracellular matrix in liver injury, regardless of the underlying disease (see Ref. 6 for review). The initial, simple paradigm of stellate cell activation first envisioned a one-way pathway from cellular quiescence to activation in early injury, with upregulation of key genes and mediators. But things are not so simple. As our understanding of stellate cell activation has advanced, subtle complexities have begun to emerge with respect to cell lineage, membrane and intracellular signaling, and transcriptional regulation of gene expression. Simple paradigms have yielded to more complex and sometimes contradictory modes of regulation in this cell's response to liver injury. This themes article will highlight recent insights into this fascinating cell type, with particular emphasis on paradoxes and controversies as the biology of stellate cell activation continues to unfold. For more comprehensive, conventional reviews the reader is referred to several recent citations (6, 16, 23).
![]() |
WHERE DO ACTIVATED STELLATE CELLS COME FROM AND WHERE DO THEY GO? |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The original view that all stellate cells are simply desmin-positive cells with perinuclear vitamin A droplets is no longer tenable. Evidence has mounted that a remarkably diverse population of mesenchymal cells exists in both normal and injured liver, with differing content of vitamin A and variable expression of intermediate filaments characteristic of myogenic and/or neural crest cells. In particular, a growing list of neural markers has been identified in stellate cells, including RhoN, glial fibrillary acidic protein, nestin, and neurotrophin receptors. As a result of this heterogeneity, it is uncertain whether all the liver's mesenchymal cells derive from the same embryonic source. It is a semantic issue as to whether they all should be termed "stellate cells." A more important question, however, is whether all harbor the same capacity to undergo either activation or apoptosis. For example, an outgrowth from primary rat stellate cells was recently characterized that was relatively resistant to apoptosis and expressed some genes that were not found in early stellate cell cultures such as the matrix glycoprotein fibulin-2 (14). Such fibulin-2 cells can also be found in vivo, but we do not know to what extent this subpopulation comprises the source of extracellular matrix in liver injury. Nonetheless, it seems likely that a greater appreciation for the functional heterogeneity of stellate cells will develop, much as we already appreciate their morphological and cytoskeletal heterogeneity.
Even more intriguing is the recognition that cellular plasticity may not be confined within the mesenchymal lineage but, rather, "transdifferentiation," or conversion from one cell lineage to another, may be possible in adult tissues. For example, in adult kidney a population of interstitial fibroblasts can develop from epithelial cells under the influence of fibroblast-specific protein-1 (29). Advances such as this one documenting the pluripotentiality of adult cell types force us to reexamine our notions of cell lineage commitment and could lead to fundamental new therapeutic approaches to cellular reconstitution in liver. Progress is also likely to accelerate as gene array techniques are applied to stellate cell systems to characterize broad changes in gene expression profiles, complemented by the impending sequencing of the entire human genome.
Neither the half-life of stellate cells in normal or injured liver nor their ultimate fate has been established with certainty. If liver injury persists, they might be replaced by other activated cells or perhaps by quiescent cells that have not yet activated. If liver injury resolves, there must be mechanisms whereby the number of activated, fibrogenic cells is diminished. Apoptosis is one potential way in which activated cells are cleared during resolution of liver injury (11); another is reversion to a quiescent phenotype. It is uncertain how either of these fates is determined; perhaps there is a "point of no return," where an activated cell can no longer be reverted to a quiescent state and instead must undergo apoptosis as injury resolves. If so, the signals marking this event could have major importance in devising new antifibrotic therapies.
![]() |
MEMBRANE RECEPTORS DURING STELLATE CELL ACTIVATION![]() |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
An emphasis on autocrine signaling has helped clarify our
understanding of ligand receptor interactions in activated stellate cells. Examples where both ligand and receptor are expressed locally include platelet-derived growth factor (PDGF), endothelin-1 (ET-1), fibroblast growth factor, vascular endothelial growth factor (VEGF), and transforming growth factor-1 (TGF-
1). For example, injury is
associated with both upregulation of the PDGF receptor and increased
autocrine PDGF production (23). Activated PDGF receptor recruits the signaling molecule Ras, followed by activation of the
extracellular signal-related kinase/mitogen-activated protein kinase
(ERK/MAPK) pathway and of focal adhesion kinase (FAK) (4, 19). Additionally, activation of phosphoinositol 3-kinase
is necessary for both mitogenesis and chemotaxis by pathways largely independent of ERK activation (21).
Receptors previously thought to be confined to sinusoidal endothelial cells have now been identified on activated stellate cells as well. For example, two VEGF receptors, Flt-1 and Flk-1, are upregulated after injury in both sinusoidal endothelial cells and stellate cells (2). Stimulation of these receptor tyrosine kinases induces cell proliferation and inhibits stellate cell contraction (22). In hypoxic conditions, both VEGF and Flt-1 mRNAs are rapidly induced in stellate cells, establishing an autocrine and paracrine loop supporting angiogenesis (3).
In some cases, receptors are not upregulated during activation but their subtypes change, with important functional consequences. For example, two G protein-coupled ET-1 receptors (ETA and ETB) are expressed by both quiescent and activated stellate cells. However, the amount and relative prevalence of these receptors changes with cellular activation, and each mediates divergent responses (24). In cell culture, ET-1 stimulates proliferation of quiescent stellate cells but is growth inhibitory toward activated cells. Proliferative responses in quiescent cells are attributed to the ETA receptor and correlate with activation of MAPK and a rapid increase in intracellular Ca2+ (24). In contrast, growth inhibition by ET-1 toward activated stellate cells is mediated by the ETB receptor and correlates with increased prostaglandin (PG) synthesis and a rise in intracellular cAMP levels, which reduces activation of ERK and c-jun kinase (JNK). The increased PG and cAMP also provoke a large increase in ETB receptor expression, suggesting a positive feedback loop that amplifies the growth inhibition by ET-1 (18).
Signals that inhibit activation are increasingly recognized even in early stellate cell activation. These may provide an important "brake" on the cascade of activation, limiting the cellular response to an injury if it is brief and self-limited. For example, although mitogen stimulation with either PDGF or thrombin on activated human stellate cells leads to increased cell proliferation, it also elevates PG and cAMP that in turn upregulates ETB receptors. Thus the overall proliferative effect of PDGF on activated stellate cells in vitro is counterbalanced by the opposing growth inhibitory effects of ETB receptor stimulation (17). A recent in vivo study demonstrated that treatment of cirrhotic rats with a mixed ETA/B receptor antagonist led to increased collagen deposition (25). This finding supports the concept that the ETB receptor may play a role in an autocrine loop that counteracts fibrogenesis through its growth-inhibitory effects. It has not yet been determined whether specific ETA receptor antagonists modulate fibrosis.
The regulation of vascular tone by hepatic stellate cells reflects the balance between contractility and vasodilation. Several receptors mediating contractility have been identified recently in addition to endothelin receptors. These include receptors for arginine vasopressin, angiotensin II, thrombin, and thromboxane. Counteracting these contractile stimuli is not only the well-characterized vasodilator nitric oxide but also two natriuretic peptide receptors, NPR-A and NPR-B, that bind the circulating vasodilators atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) (9, 30). Both are guanylate cyclase receptors that, on stimulation, lead to an increase in the intracellular second messenger cGMP. Activation of either receptor blunts the contractile responses elicited by ET-1 or thrombin. This relaxation correlates with diminished influx of intracellular Ca2+. CNP also inhibits stellate cell growth and is associated with a reduction of ERK and JNK activity and diminished DNA binding by the transcription factor AP-1. This suggests that CNP activation of NPR-B receptors may counteract both fibrogenesis and contractile stimuli that lead to portal hypertension.
Stellate cell receptors signal in response to more than cytokines.
Signals from the extracellular matrix also play a critical role in
cellular quiescence and activation. Integrins, heterodimeric proteins
consisting of an - and a
-chain, interact with extracellular matrix molecules; their specificity is defined by their subunit composition. Several integrins and their downstream effectors have been
identified in stellate cells, including
1
1,
2
1, av
1, and a6
4
(23).
In addition to the classic integrin matrix receptors, a new paradigm has been uncovered in which a tyrosine kinase receptor mediates stellate cell interactions with the extracellular matrix. The discoidin domain receptor 2 (DDR2) has been cloned from activated stellate cells and interacts with fibrillar collagens (2, 28). The identification of DDR2 mRNA and protein in activated stellate cells suggests that it may be a key receptor in hepatic fibrosis. Because fibrillar collagens are produced by activated stellate cells, the DDR2 receptor signals in response to an autocrine stimulus.
There are likely to be still more extracellular matrix receptors discovered with important roles in stellate cell quiescence and activation. For example, a splice variant of fibronectin containing the EIIIA region activates stellate cells in early liver injury (12), but its receptor has not been characterized. Identification of a putative EIIIA Fn receptor could provide a key target for antifibrotic therapy.
Stellate cells also express receptors that modulate the local
inflammatory milieu. They express cell adhesion molecules (CAM) that
recruit immune cells during tissue repair. Intercellular adhesion
molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are
rapidly induced after CCl4 administration in rodents, which
precedes mononuclear cell infiltration (13). The
inflammatory cytokine tumor necrosis factor- (TNF-
) induces
ICAM-1 and VCAM-1 expression severalfold, whereas TGF-
1 reduces
their expression. The recruitment of inflammatory cells that express
ICAM-1 and VCAM-1 ligand may have two important consequences,
1) neutralization of toxic stimuli and 2)
paracrine stimulation of stellate cell activation and fibrogenesis.
![]() |
TRANSCRIPTION FACTORS![]() |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Control of gene regulation by transcription is an essential mode of determining cell fate and activity. To date, the major insights into stellate cell biology have been in understanding the production of extracellular matrix and the roles of cytokines and their receptors. Yet it is the complex system of tissue-specific gene expression that holds the key to biological activity in virtually all mammalian systems. Thus far, however, no unique modes of gene regulation have been uncovered in stellate cells. Instead, progress in understanding transcriptional regulation in this cell type has been marked by incremental advances and by revealing subtle variations of regulatory mechanisms already unearthed in other cell types.
Nuclear factor-B (NF-
B) has been the most extensively studied
transcription factor to date in stellate cells, owing to the variety of
tools available to inhibit its activity and the rapid advances in
understanding this factor in other cell types. The complexity of its
regulation provides a cautionary tale for trying to develop simplistic
paradigms to understand transcription in stellate cells. The NF-
B
family of transcription factors are related by their Rel homology
domain (RHD) and comprise at least five members, including p65 (RelA),
p50, p52, RelB, and c-Rel, that form homo- or heterodimers that bind to
DNA. In most cell types, NF-
B is found in the cytoplasm as an
inactive dimer bound to one of the I
B inhibitory proteins (I
B
or I
B
) that mask its nuclear localization signal (NLS).
Phosphorylation of I
B
leads to its ubiquitinylation and
degradation by the proteasome. The active NF-
B dimer then
translocates into the nucleus. Reagents that block I
B
degradation
have been used to inhibit NF-
B activity to study its functional role.
The NF-B dimers p65:p65 and p50:p65 have been identified in stellate
cells. Recently, an NF-
B DNA binding complex consisting of
potentially novel Rel-like factors has been detected (5). This complex is maintained at basal levels by an autocrine-derived factor from activated cells and is upregulated by TNF-
. The
physiological significance of these different NF-
B dimers is not yet
clear. I
B
expression is reduced during cellular activation
consistent with an increase NF-
B activity. I
B
expression is
transiently reduced but later replenished with a putative
hypophosphorylated form that, rather than inhibiting NF-
B activity,
shields it from I
B
interaction. Additionally, Bcl 3, a member of
the I
B family that like I
B
can function as a positive
regulator, is also upregulated in activated cells. Thus both I
B
and Bcl 3 may sustain the basal activation of NF-
B.
NF-B activity can be further induced by cytokines in activated but
not quiescent HSCs. Induction by TNF-
and interleukin (IL)-1
leads to the expression of ICAM-1, IL-6, and macrophage inflammatory
protein-2 (MIP-2) in rats (10). In human HSCs, activation
of NF-
B by ET-1 or TNF-
leads to increased COX-2, which blocks
cell proliferation (8). NF-
B activity also protects HSCs and other cell types against apoptosis through as yet uncertain mechanisms. Finally, NF-
B activation by TNF-
also inhibits
expression of the
1(I) collagen gene (27).
Collectively, these findings document a persistent level of NF-
B
maintained by an autocrine factor in activated HSCs that can be further
upregulated by cytokines. Thus extracellular factors determine the
state of NF-
B activation, the extent of which dictates the
physiological response.
Exciting advances have been made in understanding peroxisome
proliferator-activated receptors (PPARs), a family of transcription factors belonging to the nuclear receptor superfamily. For example, PPAR- is predominantly expressed in adipose tissue, where it regulates lipid metabolism and adipocyte differentiation. Yet PPAR-
is also expressed in human HSCs, and its activity is reduced during
activation in culture (7). PPAR-
functions as a
heterodimer with another nuclear receptor, 9-cis retinoic
acid (9-cisRA) receptor (RXR). PPAR-
ligands
15-deoxy-
12,14 PGJ2 (15d-PGJ2)
and ciglitizone decrease PDGF-induced proliferation of activated HSCs
and inhibit
-smooth muscle actin expression during HSC activation
(20). This suggests that reduced transcriptional activity of PPAR-
might augment HSC activation and modulate
mitogen-induced proliferation in activated cells. Furthermore, PGs
produced by stellate cells through the upregulation of COX-2 expression
may exert autocrine effects through PPAR-
.
We have recently cloned a novel Krüppel-like factor (KLF),
Zf9/COPEB/GBF (recently renamed KLF6), as an
immediate-early gene induced in stellate cells after acute liver injury
(26). This zinc finger transcription factor has a number
of potential transcriptional targets including collagen 1(I),
TGF-
1 and its receptors, as well as urokinase type plasminogen
activator (uPA). Most recently, however, an antiproliferative activity
of this factor has been described (15). Why would a gene
upregulated in the midst of stellate cell activation inhibit
proliferation? Is this another example of a counterregulatory
"brake" to limit the extent of activation? The answer is not clear,
but this paradox further underscores the complexity of gene regulation
in stellate cell activation and hints at the challenge in dissecting
modes of cellular regulation.
![]() |
WHITHER THE FUTURE? |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
As the complexity of stellate cell activation becomes increasingly apparent, the tools available to clarify its regulation have also advanced. With the availability of proteomics, gene array, and bioinformatics analyses, biological processes such as stellate cell activation need no longer be viewed as isolated, parallel pathways but rather as highly integrated events in which many genes are regulated and proteins are modified simultaneously and interdependently. Gene array technology has uncovered patterns of disease in which hundreds of genes are jointly regulated, for example, in patients with subtypes of B cell lymphoma (1). Approaches like this promise to revolutionize the way we view cellular responses and to create new paradigms of regulation that are not even conceivable based on current knowledge. Those who study stellate cell activation are likely to be major beneficiaries of such advances in the coming years.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: S. L. Friedman, Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave, Rm. 1170F, New York, NY 10029 (E-mail: frieds02{at}doc.mssm.edu).
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Alizadeh, AA,
Eisen MB,
Davis RE,
Ma C,
Lossos IS,
Rosenwald A,
Boldrick JC,
Sabet H,
Tran T,
Yu X,
Powell JI,
Yang L,
Marti GE,
Moore T,
Hudson J, Jr,
Lu L,
Lewis DB,
Tibshirani R,
Sherlock G,
Chan WC,
Greiner TC,
Weisenburger DD,
Armitage JO,
Warnke R,
and
Staudt LM.
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.
Nature
403:
503-511,
2000[ISI][Medline].
2.
Ankoma-Sey, V,
Matli M,
Chang KB,
Lalazar A,
Donner DB,
Wong L,
Warren RS,
and
Friedman SL.
Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing.
Oncogene
17:
115-121,
1998[ISI][Medline].
3.
Ankoma-Sey, V,
Wang Y,
and
Dai Z.
Hypoxic stimulation of vascular endothelial growth factor expression in activated rat hepatic stellate cells.
Hepatology
31:
141-148,
2000[ISI][Medline].
4.
Carloni, V,
Pinzani M,
Giusti S,
Romanelli RG,
Parola M,
Bellomo G,
Failli P,
Hamilton AD,
Sebti SM,
Laffi G,
and
Gentilini P.
Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on ras in human hepatic stellate cells.
Hepatology
31:
131-140,
2000[ISI][Medline].
5.
Elsharkawy, AM,
Wright MC,
Hay RT,
Arthur MJ,
Hughes T,
Bahr MJ,
Degitz K,
and
Mann DA.
Persistent activation of nuclear factor-B in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of I
B family proteins.
Hepatology
30:
761-769,
1999[ISI][Medline].
6.
Friedman, SL.
Molecular regulation of hepatic fibrosis; an integrated cellular response to tissue injury.
J Biol Chem
275:
2247-2250,
2000
7.
Galli, A,
Crabb D,
Price D,
Ceni E,
Salzano R,
Surrenti C,
and
Casini A.
Peroxisome proliferator-activated receptor transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells.
Hepatology
31:
101-108,
2000[ISI][Medline].
8.
Gallois, C,
Habib A,
Tao J,
Moulin S,
Maclouf J,
Mallat A,
and
Lotersztajn S.
Role of NF-B in the antiproliferative effect of endothelin-1 and tumor necrosis factor-
in human hepatic stellate cells. Involvement of cyclooxygenase-2.
J Biol Chem
273:
23183-23190,
1998
9.
Gorbig, MN,
Gines P,
Bataller R,
Nicolas JM,
Garcia- Ramallo E,
Tobias E,
Titos E,
Rey MJ,
Claria J,
Arroyo V,
and
Rodes J.
Atrial natriuretic peptide antagonizes endothelin-induced calcium increase and cell contraction in cultured human hepatic stellate cells.
Hepatology
30:
501-509,
1999[ISI][Medline].
10.
Hellerbrand, C,
Jobin C,
Licato LL,
Sartor RB,
and
Brenner DA.
Cytokines induce NF-B in activated but not in quiescent rat hepatic stellate cells.
Am J Physiol Gastrointest Liver Physiol
275:
G269-G278,
1998
11.
Iredale, JP,
Benyon RC,
Pickering J,
McCullen M,
Northrop M,
Pawley S,
Hovell C,
and
Arthur MJ.
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
12.
Jarnagin, WR,
Rockey DC,
Koteliansky VE,
Wang SS,
and
Bissell DM.
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].
13.
Knittel, T,
Dinter C,
Kobold D,
Neubauer K,
Mehde M,
Eichhorst S,
and
Ramadori G.
Expression and regulation of cell adhesion molecules by hepatic stellate cells (HSC) of rat liver: involvement of HSC in recruitment of inflammatory cells during hepatic tissue repair.
Am J Pathol
154:
153-167,
1999
14.
Knittel, T,
Kobold D,
Saile B,
Grundmann A,
Neubauer K,
Piscaglia F,
and
Ramadori G.
Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential.
Gastroenterology
117:
1205-1221,
1999[ISI][Medline].
15.
Li, D,
Eng F,
and
Friedman SL.
Zf9 (KLF6) regulates cell proliferation and apoptosis in activated stellate cells and NIH3T3 cells (Abstract).
Hepatology
30:
393A,
1999[ISI].
16.
Li, D,
and
Friedman SL.
Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy.
J Gastroenterol Hepatol
14:
618-633,
1999[ISI][Medline].
17.
Mallat, A,
Gallois C,
Tao J,
Habib A,
Maclouf J,
Mavier P,
Preaux AM,
and
Lotersztajn S.
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
18.
Mallat, A,
Preaux AM,
Serradeil-Le Gal C,
Raufaste D,
Gallois C,
Brenner DA,
Bradham C,
Maclouf J,
Iourgenko V,
Fouassier L,
Dhumeaux D,
Mavier P,
and
Lotersztajn S.
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
19.
Marra, F,
Arrighi MC,
Fazi M,
Caligiuri A,
Pinzani M,
Romanelli RG,
Efsen E,
Laffi G,
and
Gentilini P.
Extracellular signal-regulated kinase activation differentially regulates platelet-derived growth factor's actions in hepatic stellate cells, and is induced by in vivo liver injury in the rat.
Hepatology
30:
951-958,
1999[ISI][Medline].
20.
Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G,
Bonacchi A, Caporale R, Laffi G, Pinzani M, and Gentilini P. Ligands of peroxisome-proliferator activated receptor gamma modulate
profibrogenic and proinflammatory actions of hepatic stellate cells.
Gastroenterology. In press.
21.
Marra, F,
Gentilini A,
Pinzani M,
Choudhury GG,
Parola M,
Herbst H,
Dianzani MU,
Laffi G,
Abboud HE,
and
Gentilini P.
Phosphatidylinositol 3-kinase is required for platelet-derived growth factor's actions on hepatic stellate cells.
Gastroenterology
112:
1297-1306,
1997[ISI][Medline].
22.
Mashiba, S,
Mochida S,
Ishikawa K,
Inao M,
Matsui A,
Ohno A,
Ikeda H,
Nagoshi S,
Shibuya M,
and
Fujiwara K.
Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with upregulation of FLT tyrosine kinase receptor family, FLT-1.
Biochem Biophys Res Commun
258:
674-678,
1999[ISI][Medline].
23.
Pinzani, M,
Marra F,
and
Carloni V.
Signal transduction in hepatic stellate cells.
Liver
18:
2-13,
1998[ISI][Medline].
24.
Pinzani, M,
Milani S,
De FR,
Grappone C,
Caligiuri A,
Gentilini A,
Tosti GC,
Maggi M,
Failli P,
Ruocco C,
and
Gentilini P.
Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells.
Gastroenterology
110:
534-548,
1996[ISI][Medline].
25.
Poo, JL,
Jimenez W,
Maria Munoz R,
Bosch-Marce M,
Bordas N,
Morales-Ruiz M,
Perez M,
Deulofeu R,
Sole M,
Arroyo V,
and
Rodes J.
Chronic blockade of endothelin receptors in cirrhotic rats: hepatic and hemodynamic effects.
Gastroenterology
116:
161-167,
1999[ISI][Medline].
26.
Ratziu, V,
Lalazar A,
Wong L,
Dang Q,
Collins C,
Shaulian E,
Jensen S,
and
Friedman SL.
Zf9, a Krüppel-like transcription factor upregulated in vivo during early hepatic fibrosis.
Proc Natl Acad Sci USA
95:
9500-9505,
1998
27.
Rippe, RA,
Schrum LW,
Stefanovic B,
Solis-Herruzo JA,
and
Brenner DA.
NF-B inhibits expression of the
1(I) collagen gene.
DNA Cell Biol
18:
751-761,
1999[ISI][Medline].
28.
Shrivastava, A,
Radziejewski C,
Campbell E,
Kovac L,
McGlynn M,
Ryan TE,
Davis S,
Goldfarb M,
Glass DJ,
Lemke G,
and
Yancopoulos GD.
An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors.
Mol Cell
1:
25-34,
1997[ISI][Medline].
29.
Strutz, F,
Okada H,
Lo CW,
Danoff T,
Carone RL,
Tomaszewski JE,
and
Neilson EG.
Identification and characterization of a fibroblast marker: FSP1.
J Cell Biol
130:
393-405,
1995[Abstract].
30.
Tao, J,
Mallat A,
Gallois C,
Belmadani S,
Mery PF,
Nhieu JT,
Pavoine C,
and
Lotersztajn S.
Biological effects of C-type natriuretic peptide in human myofibroblastic hepatic stellate cells.
J Biol Chem
274:
23761-23769,
1999