Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02114
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ABSTRACT |
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In view of the recent success in
pancreatic islet transplantation, interest in treating diabetes by the
delivery of insulin-producing -cells has been renewed. Because
differentiated pancreatic
-cells cannot be expanded significantly in
vitro,
-cell stem or progenitor cells are seen as a potential source
for the preparation of transplantable insulin-producing tissue. In
addition to embryonic stem (ES) cells, several potential adult
islet/
-cell progenitors, derived from pancreas, liver, and bone
marrow, are being studied. To date, none of the candidate cells has
been fully characterized or is clinically applicable, but pancreatic
physiology makes the existence of one or more types of adult islet stem
cells very likely. It also seems possible that pluripotential stem
cells, derived from the bone marrow, contribute to adult islet
neogenesis. In future studies, more stringent criteria should be met to
clonally define adult islet/
-cell progenitor cells. If this can be
achieved, the utilization of these cells for the generation of
insulin-producing
-cells in vitro seems to be feasible in the near future.
pancreatic islets; liver oval cells; embryonic stem cells; nestin; insulin; islet-like clusters; -cell; transplantation
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INTRODUCTION |
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THE PREVALENCE OF THE
DISABLING DISEASE diabetes mellitus is increasing at epidemic
proportions throughout the populations of the world. It is estimated
that 100 million individuals currently suffer from diabetes, 16 million
in the United States alone. Diabetes comes about by the progressive
failure of the -cells of the endocrine pancreas (islets of
Langerhans) to produce the hormone insulin in the amounts required to
meet the body's needs to maintain nutrient homeostasis. A lack of
insulin results in elevations in blood glucose levels (hyperglycemia)
and the subsequent development of premature cardiovascular disease,
stroke, and kidney failure. There is no currently available permanent
cure for diabetes. Blood glucose levels can be somewhat controlled by
daily insulin shots or, in moderate cases of diabetes, by oral
hypoglycemic (blood glucose-lowering) drugs. Diabetes is manifested in
two relatively distinct forms: type 1 juvenile and type 2 adult onset.
Type 1 juvenile diabetes is due to a nearly complete destruction of the
-cells by processes of autoimmunity in which the body's immune system mistakenly attacks and destroys the
-cells. The causation of
type 2 adult-onset diabetes is more complex and poorly understood, but
the
-cells fail to produce adequate amounts of insulin in the face
of the accompanying resistance of peripheral tissues to the actions of
insulin. All patients with type 1 diabetes require daily insulin shots
to survive. Twenty to thirty percent of type 2 diabetic individuals
also require exogeneous insulin to control their hyperglycemia after
oral hypoglycemic agents have failed.
Recently, hope for a permanent cure of diabetes has appeared, namely,
the transplantation of islets isolated from donor pancreata into the
livers of diabetic patients. The recent success of the Edmonton
Protocol for pancreatic islet transplantation (45, 46) has
sparked new interest in transplantation of insulin-producing cells.
However, the amount of donor islet tissue is severely limited and will
allow for the treatment of only a small fraction of patients with
insulin-dependent diabetes, <0.5% of needy recipients. Moreover, differentiated -cells cannot be expanded efficiently in vitro (24). Therefore, multiple approaches are now being
explored to generate insulin-producing cells in vitro, either by
genetic engineering of
-cells or by utilizing various potential
-cell precursor cells, stem/progenitor cells, with the ability to
grow in vitro and to differentiate into
-cells. Some promising
results have already been obtained with embryonic stem cells (ES cells) of both rodent and human origin (2, 38, 50). However, the potential use of ES cells for the treatment of diseases in humans is
beclouded in controversy because of the ethical issues.
This review will focus on the potential of adult tissue-derived stem
cells, in lieu of embryo-derived stem cells, for the treatment of
diabetes. We discuss the role of adult islet stem/progenitor cells in
normal physiology, highlight possible candidate cells isolated to date,
and describe different approaches for stem cell-based therapy. We will
also propose several criteria for the establishment of -cell
differentiation from putative stem cells, both in vitro and in vivo.
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PHYSIOLOGICAL ROLE OF ADULT ISLET PROGENITOR CELLS |
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Stem or progenitor cells are defined by their capacity for self-renewal and asymmetric cell division, which leads to their differentiation and the formation of one or more mature tissues and the preservation of the stem cell population. Pluripotential cells exist in the inner mass of the blastocyst, so-called ES cells, and in the developing gonadal ridge, germ stem cells or GSCs. In some tissues, like bone marrow or intestinal epithelium, the existence of adult stem cells has been recognized for a long time and has been studied extensively (see review in Ref. 4). For other adult tissues, like brain, muscle, liver, and the endocrine pancreas, the function of adult stem cells is less well established, although substantial evidence for their existence and potential efficacy has recently been obtained.
When the embryonic development of the pancreas is studied, several sequentially expressed transcription factors are used to identify different cell populations within the forming pancreas that buds from the endodermal epithelium of the developing foregut. The homeodomain transcription factor Pdx-1 (also known as Ipf-1, Idx-1, and Stf-1) is expressed early in pancreas development (embryonic day 8.5 in the mouse), and its expression is required for the pancreas to develop. The disruption of Pdx-1 expression in mice and humans results in pancreatic agenesis, a complete failure of the pancreas to develop (31, 52). The expression of neurogenin 3 (Ngn3), a basic helix-loop-helix transcription factor, at embryonic development day 9.5 defines the first identifiable endocrine cell precursors. From then on, a cascade of transcription factors leads to the formation of all endocrine lineages of the islets of Langerhans (see reviews in Refs. 11 and 54). Throughout fetal development, a massive expansion of pancreatic endocrine cells is achieved mainly by the proliferation and subsequent differentiation of progenitor cells, rather than by the division of fully differentiated endocrine cells (8, 32, 42).
The formation of new islet tissue via the differentiation of
stem/progenitor cells in adult pancreata was first demonstrated in
different models of pancreatic injury. This regenerative process is
called neogenesis. For example, partial pancreatectomy in rodents leads
to the neogenesis of new islets from cells residing within or adjacent
to the epithelium of pancreatic ducts (5). In another model of injury, the treatment of rodents with the drug streptozotocin (STZ), a -cell toxin, induces the regeneration of endocrine cells from intraislet progenitors (17, 21). Also, in the setting of a sudden increase in insulin demand, such as an experimental glucose
infusion, neogenesis of endocrine cells from adult progenitor cells is
a major adaptive mechanism (3). It was also shown recently
that Ngn3-expressing cells persist into postnatal life and continue to
contribute to islet cell development under normal physiological
conditions (19). However, we suggest that the Ngn3-expressing cells are probably only transitory cells in endocrine maturation and not true stem or progenitor cells capable of
self-renewal. Therefore, although the existence of adult islet
progenitor cells can be inferred from these studies, the exact nature
and location of these cells have yet to be definitively determined. It
seems likely that distinct sets of progenitor cells and pathways of neogenesis (e.g., intraislet vs. duct to islet) exist in parallel within the pancreas. In this regard, it has been shown that the islets
are polyclonal in origin (10).
A further level of complexity is added by the recent reports about the possible existence of circulating pluripotential and mobile stem cells that may take up residence within many different adult organs and tissues (4, 29). Although the uptake of circulating stem cells by the endocrine pancreas has not yet been demonstrated, the regeneration of endocrine cells from a systemic source of pluripotential stem cells seems possible.
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CANDIDATES FOR ADULT PANCREATIC STEM/PROGENITOR CELLS |
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To date, no adult pancreatic stem cell has been fully
characterized. However, several candidate cells have been identified, isolated, and partially characterized (Table
1). It is important to note that
differentiation protocols at present allow for only small amounts of
insulin production compared with pancreatic islets.
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Pancreatic Duct-Derived Stem/Progenitor Cells
Because under certain conditions islet regeneration appears to originate from the ductal epithelium (5), ductal tissue provides promising starting material for the search for islet progenitor cells. Indeed, the first report to describe in vitro-generated insulin-producing islet-like clusters (ILCs) was based on the expansion of cells from a crude preparation of mouse pancreatic ducts (44). The authors manually isolated ducts from collagenase-digested pancreata of prediabetic nonobese diabetic (NOD) mice. Rapidly growing cells could be maintained in culture for >3 yr and aggregated into clusters (ILCs), which could secrete small amounts of insulin in vitro. Upon transplantation into NOD mice, these ILCs significantly lowered the plasma glucose levels of the animals. However, the specific cells in the pancreatic ducts that are the progenitors giving rise to the insulin-producing cells were not identified or characterized.Bonner-Weir et al. (7) generated ILCs in vitro from fractions of digested human pancreata enriched for ductal tissue. When plastic adherent cells from these preparations were overlaid with Matrigel, they formed cysts and clusters (cultured human islet buds, or CHIBs). Most cells in these aggregates were positive for the ductal marker cytokeratin 19, and others showed immunoreactivity for insulin and other islet hormones. The insulin content of the cultures increased over time, and a low level of glucose-responsive insulin secretion was observed in vitro. However, the capacity to expand the cultivated tissue was limited.
Nestin-Positive Islet-Derived Progenitor Cells
Our laboratory has reported that cells expressing the intermediate filament protein nestin, a marker of neural stem cells, can be isolated from human and rodent islets and expanded extensively in vitro. Insulin, glucagon, and Pdx-1/Ipf-1 expression, as well as low-level insulin secretion, can be detected in cultures of nestin-positive islet-derived stem/progenitor cells (NIPs) after addition of differentiating cytokines and growth factors (1, 64). Furthermore, the expression of other neuroendocrine, hepatic, and pancreatic exocrine genes can be demonstrated by RT-PCR (64). These cells also form ILCs in vitro, a process that is markedly enhanced by the addition of the insulinotropic, neogenic hormone glucagon-like peptide-1 (GLP-1) (1).Whereas nestin was initially believed to be a marker restricted
to neural and muscular progenitor cells (63), it is now recognized that certain mesenchymal cells also express nestin under
selected conditions. With regard to the pancreas, recent reports
demonstrate the expression of nestin in embryonic mesenchyme (48) and adult pancreatic stellate cells, as well as in
proliferating vascular endothelium (36). Data from our own
laboratory confirm these observations. Thus nestin in the pancreas is
not an exclusive marker for islet stem/progenitor cells, but rather,
some nestin-positive cells have the potential for the differentiation
into pancreatic (islet) endocrine cells, including cells that produce
insulin. This finding is also supported by the observation that nestin expression occurs as an intermediate step in the differentiation of
-cells from ES cells (38). We also demonstrated
recently, by flow cytometry cell sorting, that 1-3% of NIPs have
a side-population phenotype similar to undifferentiated bone marrow
stem cells (18, 37). This finding suggests that NIPs might
contain a subpopulation of immature stem cells with a differentiating
potential that extends beyond the endocrine pancreas, possibly as part
of a population of adult multipotential/pluripotential stem cells.
Hepatic Oval Cells
The close anatomic association of pancreas and liver development from the primitive foregut during embryogenesis has prompted attempts to isolate pancreatic progenitor cells from adult liver. Recently, Yang et al. (60) reported the in vitro generation of ILCs from rat liver preparations enriched for hepatic oval cells. Oval cells are considered to be hepatic stem cells that can give rise to hepatocytes and bile duct cells (41). The authors induced in vivo proliferation of oval cells by a chemical injury of the liver and then enriched them to over 95% by flow cytometry cell sorting. After the in vitro expansion of the oval cells and their formation into ILCs, the expression of endocrine hormones and several otherMultipotent Adult Progenitor Cells
Recently, the laboratory of Catherine Verfaillie (Jiang et al., Ref. 29) reported the successful expansion of cells from the adult bone marrow that have the potential to differentiate into ectodermal (neuronal), mesodermal (vascular endothelium), and endodermal (liver) cell types in vitro. In vivo, these cells show similar plasticity and contribute to multiple tissues after transplantation (29). The multipotent adult progenitor cells (MAPCs) can also be isolated from brain and muscle tissue (30) and may exist in every tissue of the body. The differentiation of MAPCs into pancreatic endocrine cells has not yet been shown. If we consider, however, that MAPCs can be transdifferentiated into hepatocyte-like cells with remarkable functional properties in vitro (47), the generation of pancreatic endocrine cells from MAPCs seems to be within reach. ![]() |
STEM CELL STIMULATORS AND DIFFERENTIATORS |
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Multipotential stem/progenitor cells can be induced to proliferate
and to differentiate when exposed in vitro to certain growth factors or
cytokines. A cell line (AR42J) derived from pancreatic ducts can be
converted into insulin-producing cells by exposure to the growth
factors betacellulin and activin A (39) or to the hepatic
growth factor (40). Cells derived from pancreatic islets
increase their rates of proliferation in the presence of basic
fibroblast and epidermal growth factors (bFGF and EGF)
(64). These cells can then be differentiated into ILCs by
the removal of bFGF and EGF and the addition of differentiating
factors such as activin A, betacellulin, hepatic growth factor
(64), or the insulinotropic neogenic hormone GLP-1
(1). Nicotinamide is often used to increase the number of
-cells and to boost the production of insulin (44).
GLP-1 appears to be a particularly effective agent for inducing the
differentiation of both NIPs (1) and duct cells into
insulin-producing cells. Notably, GLP-1 induces the expression of the
homeodomain protein Pdx-1/Ipf-1 in the stem/progenitor (1)
and duct cells (26, 51, 59, 62), which appears to be
essential for their differentiation into
-cells. GLP-1 receptors
have been identified on NIPs (1). It is believed that the
activation of the receptor by GLP-1 activates Pdx-1 both by its
phosphorylation via MAP kinase pathways and by effecting its
translocation into the nucleus (9, 13, 27, 57). In many
respects, Pdx-1 is a "master regulator" of pancreas development and
function (see reviews in Refs. 11, 22, and 23). Pdx-1 is required for the pancreas to develop and is
a key regulator of the expression of many
-cell genes, including the
insulin gene. The forced expression of Pdx-1 in a pancreatic ductal
cell line renders the cells responsive to GLP-1, resulting in their
differentiation into insulin-producing cells (26). Remarkably, the infection of a subpopulation of liver cells with an
adenoviral vector expressing Pdx-1 converts the cells into functional
-cells and restores glycemic control in mice rendered diabetic by
their treatment with STZ (15). These studies suggest that,
in the milieu of a stem cell, Pdx-1 in and by itself may be capable of
programming the genome of the stem cell to express the set of genes
required to establish a fully functional
-cell.
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POSSIBLE ORIGINS OF PANCREAS AND OTHER ADULT ORGAN-DERIVED STEM CELLS |
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Although the existence of pluripotential or multipotential stem/progenitor cells in adult organs appears to be relatively well established, the intriguing question remains as to how these cells actually got there. First, they may represent a population of cells that are preserved throughout development in every single organ. These cells would have maintained many properties of pluripotential blastocyst cells and could participate in local tissue repair throughout the lifespan of the organism. A second possibility is that the new stem cells continuously reach different organs through the circulation; the bone marrow may contain a self-renewing population of multipotent stem cells that are continuously released into the circulation along with the different types of leukocytes. It is tempting to speculate that stem cells are an essential component of these circulating bone marrow surveillance cells and are prepared to home in on areas of injured tissues to participate in tissue repair and regeneration. One notion is that a normal physiological function of circulating stem cells is to replace differentiated cells that have a high turnover, such as intestinal mucosa, skin, and hair follicles (4). But their function may more importantly be to sense and home in on injured tissues. However, the naturally occurring population of circulating stem cells is likely to have a limited capacity to deal with severe injuries. This might be especially true with increasing age. This notion is consistent with the clinical concept of age-dependent loss of "organ reserve," the capacity to heal from injury and to replace injured tissue with functional new tissue.
There is considerable experimental evidence in support of the idea that circulating stem cells originating from the bone marrow populate adult organs (see review in Ref. 4). Patients transplanted with gender-mismatched hematopoietic stem cells (HSCs) developed a substantial degree of chimerism (up to 7%) in the liver, skin, and gastrointestinal tract, leading to the conclusion that circulating stem cells can differentiate into mature hepatocytes and epithelial cells of the skin and gastrointestinal tract (34). The mesenchymal MAPCs in the bone marrow recently described by Jiang et al. (30) have now been found in brain and muscle. Remarkably, gene expression profiling on oligonucleotide microarrays revealed that the genes expressed by MAPCs derived from brain, muscle, and bone marrow are 99.99% identical. These findings strongly indicate that the MAPCs found in these three different organs are the same cells and are consistent with the circumstance that MAPCs are produced in the bone marrow, delivered into the circulation, and taken up by brain and muscle. This mechanism for the distribution of stem cells is further supported by several studies in rodents with specific tissue injuries in which subpopulations of HSCs were administered systemically. In rodent models of heart attack (28, 33), brain stroke (25, 61), muscular dystrophy (20), and liver injury (35, 56), the cells rapidly home in on the sites of injuries and then differentiate into the resident tissue phenotype. The extent of repopulation of some of the injured tissues was substantial. In the mouse model of brain stroke, an average 34% of the vascular endothelial cells were derived from HSCs (25). Sixty percent or more of the liver tissue of some mice with liver injury consisted of hematopoietic donor cells (56).
The property of stem cells to colonize injured tissue is also demonstrated by the recently reported study by Quaini et al. (43). Female donor hearts transplanted into male recipients rapidly became chimeric; within 4-28 days after the transplant, 15, 12, and 9% of cells in myocytes, arterioles, and capillaries, respectively, of the donor heart consisted of recipient male gender cells. Although the origin of these recipient cells was uncertain, it was suggested that they likely came from circulating stem cells of the host recipient rather than from migration of cells into the heart from the recipient tissue adjacent to the anastomoses of the donor heart (43). It is noteworthy that the effective repair of the genetically determined mouse model of liver injury, due to an inborn error of tyrosine metabolism, has also been achieved by the administration of a population of pancreas-derived cells (55). Although the pancreatic cells that resulted in a repair of the liver were not characterized, it seems rather likely that the cells are related to the duct (7, 44) and/or are islet-derived (1, 64) stem/progenitor cells. The two models proposed for the origin of adult tissue-derived stem cells are not necessarily mutually exclusive. It seems reasonable to speculate that the pluripotent stem cells in the bone marrow are derived by lifetime self-renewal of the original pluripotent cells of the blastocyst and that tissue-specific multipotent progenitor cells with restricted differentiation capacity also exist.
The physiological and cellular mechanisms responsible for the "homing
in" of circulating stem cells into areas of tissue injury is not
understood. However, ligand-receptor interactions may be at play, as
suggested by Jackson et al. (28), who conjectured that the vascular endothelial growth factor (VEGF) expressed in the
injected HSCs may have directed them to the experimentally infarcted
myocardium that expressed the VEGF receptor (Flk-1). In this regard, it
is interesting to postulate that the expression of the GLP-1 receptor
by pancreas-derived stem cells (NIPs) may promote homing in to the
pancreatic islets, whose surface (mantle) is enriched in -cells that
express the proglucagon (GLP-1) gene. It seems possible to imagine that
one function of the
-cells may be to "capture" circulating stem
cells by virtue of their interaction with the GLP-1 hormone expressed
by
-cells. If, indeed, the stem/progenitor cells in the pancreas
originate from the bone marrow via the circulation, then it is possible
that there may be separate distinct functions for the duct-derived
compared with the islet-derived stem cells (Fig.
1). We envision that, once a
pluripotential stem cell finds a niche in a particular tissue, it
receives initial instructions from the environment to differentiate toward that particular tissue. Thereby, we suggest that the stem cells
that are captured from the circulation by the ducts are instructed to
become new islets, a concept consistent with the longstanding
observations that new islets continue to bud off from the pancreatic
ducts, the classic description of islet neogenesis. In contrast to the
formation of new whole islets from the ducts, we conjecture that the
stem cells that land in the islets are instructed to become new
-cells to replace those that undergo natural senescence. This
process of
-cell neogenesis in fully formed islets may be different
from the process of islet neogenesis that takes place in the ducts.
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ENVISIONED APPROACH FOR STEM CELL-DERIVED THERAPIES FOR DIABETES |
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At least two distinct approaches to the use of stem cells seem
feasible for the treatment of diabetes (Fig.
2). One would be to procure appropriate
donor tissue (pancreas biopsy) from a diabetic "to-be" recipient of
islet transplants into the liver. The stem cells could be isolated from
the biopsied tissue, expanded by culture in vitro, and differentiated
into ILCs, or even into fully differentiated islets, once the
technology to do so is available. Such a commercial source for
"growing" unlimited numbers of islets would alleviate the acute
shortage of donor pancreata from which islets for transplantation are
prepared.
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A second approach, quite different from the preparation of islets from
stem cells in vitro, is to administer multipotential stem
cells systemically to patients with type 1 diabetes and to depend on
their properties to home in on injured tissues, as shown in the rodent
studies. The cells would be delivered into the circulation as a
"cellular medicine" by short infusions or injections. This approach
would require the isolation and purification of a homogenous population
of stem/progenitor cells that are selected for their high propensity to
want to become islet or -cells. The coadministration during and
after islet transplantation of stem cell stimulators/differentiators, such as GLP-1, would possibly enhance the efficiency of engraftment and
the establishment of a permanent self-renewing population of
stem/progenitor cells to provide a continued source of functional
-cells.
Aspects of the proposed stem cell therapy that are important to
recognize are the recent findings of the capacity of stem cells to
induce tissue tolerance, in which the host recipient recognizes
transplanted foreign tissue derived from stem cells as self, and the
graft is not rejected. Such induction of tissue tolerance across both
allogenic and xenogenic boundaries without a requirement for
immunosuppression has been demonstrated in rodents in which mixed
chimerism has been established by marrow transplants (see reviews in
Refs. 53 and 58) and in rat and mouse models transplanted
with stem cells (14, 49). It seems possible that stem cell
transplants may also be able to resist the autoimmunity of type 1 diabetes, even after they differentiate into -cells in the
recipient. Ferber et al. (16) recently reported the
successful transdifferentiation of liver cells into fully functional
-cells that achieve glycemic control in the NOD mouse model of
autoimmunity type 1 diabetes.
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SUGGESTED CRITERIA TO DEFINE A PANCREAS-DERIVED STEM CELL |
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All studies of pancreatic endocrine progenitor cells published to
date, including our own, fall short in fully defining their properties
as stem/progenitor cells. To advance our understanding of islet biology
and, more importantly, to isolate -cell stem/progenitors that will
be clinically applicable, more rigorous methods are necessary.
Therefore, we would like to suggest a set of criteria that should be
met in future studies. 1) The stem or progenitor cell should
be clonally isolated or marked; "enrichment" of a certain cell type
alone is not sufficient. 2) In vitro differentiation to a
fully functional
-cell should be unequivocally established. Insulin
expression per se does not make a particular cell a
-cell. The
expression of many other markers of
-cells (e.g., Pdx1/Ipf1, GLUT2,
and glucokinase) or other endocrine islet cells should be demonstrated.
3) Ultrastructural studies should confirm the formation of
mature endocrine cells by identification of characteristic insulin
secretory granules. 4) The in vitro function of endocrine cells, differentiated from stem cells, should be reminiscent of the
natural counterparts. For
-cells, this would imply a significant glucose-responsive insulin secretion, adequate responses to incretin hormones and secretagogues, and the expected electrophysiological properties. 5) In vivo studies in diabetic animals should
demonstrate a reproducible and durable effect of the
stem/progenitor-derived tissue on the attenuation of the diabetic
phenotype. It should also be demonstrated that removal of the stem
cell-derived graft after a certain period of time leads to reappearance
of the diabetes. 6) For future clinical use, the
tumorgenicity of stem/progenitor-derived tissue should be determined.
Additionally, immune responses toward the transplanted cells should be examined.
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CONCLUSIONS |
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To date, no fully defined and clinically applicable adult -cell
stem/progenitor has been isolated. Nevertheless, studies of the
development and the physiology of the pancreas make the existence of
pancreatic stem/progenitor cells highly likely. Additionally, several
potential candidate cells are being studied, and although more rigid
experimental criteria have yet to be met, the published results look
highly promising. The utilization of adult stem/progenitor cells for
the generation of insulin-producing
-cells in vitro and their use
for the treatment of diabetes, therefore, seem to be feasible in the
near future.
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ACKNOWLEDGEMENTS |
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We thank our colleagues in the Laboratory of Molecular Endocrinology for their support and helpful suggestions, Dr. Melissa K. Thomas for critical reading of the manuscript and suggestions, Robyn Blacken for expert experimental assistance, and Melissa Fannon for help in the preparation of the manuscript.
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FOOTNOTES |
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This study was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-30834, DK-55365, and DK-60125. A. Lechner is a research fellow supported by the Deutsche Forschungsgemeinschaft. J. F. Habener is an investigator with the Howard Hughes Medical Institute.
Address for reprint requests and other correspondence: J. F. Habener, Laboratory of Molecular Endocrinology, Massachusetts General Hospital, 55 Fruit St., WEL 320, Boston, MA 02114 (E-mail: jhabener{at}partners.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00393.2002
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