Review: Pancreatic β-Cell Neogenesis Revisited
Copyright c Taylor and Francis Inc.
Review : Pancreatic ?-Cell Neogenesis Revisited
Maryline Paris 0
Ce?cile Tourrel-Cuzin 0
Ce?dric Plachot 0
Alain Ktorza 0
0 Laboratoire de Physiopathologie de la Nutrition , Universite Paris 7, Paris , France
?-cell neogenesis triggers the generation of new ?-cells from precursor cells. Neogenesis from duct epithelium is the most currently described and the best documented process of differentiation of precursor cells into ?-cells. It is contributes not only to ?-cell mass expansion during fetal and nonatal life but it is also involved in the maintenance of the ?-cell mass in adults. It is also required for the increase in ?-cell mass in situations of increase insulin demand (obesity, pregnancy). A large number of factors controlling the differentiation of ?-cells has been identified. They are classified into the following main categories: growth factors, cytokine and inflamatory factors, and hormones such as PTHrP and GLP-1. The fact that intestinal incretin hormone GLP-1 exerts a major trophic role on pancreatic ?-cells provides insights into the possibility to pharmacologically stimulate ?-cell neogenesis. This could have important implications for the of treatment of type 1 and type 2 diabetes. Transdifferentiation, that is, the differentiation of already differentiated cells into ?-cells, remains controversial. However, more and more studies support this concept. The cells, which can potentially ?transdifferentiate? into ?-cells, can belong to the pancreas (acinar cells) and even islets, or originate from extra-pancreatic tissues such as the liver. Neogenesis from intra-islet precursors also have been proposed and subpopulations of cell precursors inside islets have been described by some authors. Nestin positive cells, which have been considered as the main candidates, appear rather as progenitors of endothelial cells rather than ?-cells and contribute to angiogenesis rather than neogenesis. To take advantage of the different differentiation processes may be a direction for future cellular therapies. Ultimately, a better understanding of the molecular mechanisms involved in ?-cell neogenesis will allow us to use any type of differentiated and/or undifferentiated cells as a source of potential cell precursors.
Ductal Cell Precursors; GLP-1; Intra-Islet Precursors; Nestin; Transdifferentiation
?-cell neogenesis is the mechanism that triggers the
generation of new ?-cells from precursor cells. Although this
definition is largely accepted, the origin and the nature of the cell
precursors are controversial. For a long time, ?-cell neogenesis
was considered as a process restricted to the mechanism
allowing morphological and functional changes of ductal epithelial
undifferentiated precursors into ?-cell [
]. However, recent
data and new concepts suggest that ?-cell precursors could not
be located only within pancreatic ducts [
Taken into account the most recent findings and hypotheses,
new ?-cells could potentially originate from:
1. Ductal cells by ductal neogenesis.
2. Already differentiated pancreatic cell (i.e., exocrine, acinar
or ductal) or extra-pancreatic cells through a mechanism so
3. An islet precursor cell by intra-islet neogenesis.
Figure 1 summarizes these different possibilities.
In this review we will focus on the mechanism and on the
different potential precursors involved in ?-cell neogenesis. We
will also discuss the extent to which a better understanding
of the mechanisms of ?-cell neogenesis could help us in the
possible outcomes for future treatments of diabetes based upon
NEOGENESIS FROM DUCT EPITHELIUM
Neogenesis from duct epithelium is the most currently
described and the best documented process by which progenitor
cells can differentiate into endocrine cells.
During fetal life [
], and in the neonatal period [
?-cell differentiation is the major contributor to ?-cell mass
expansion. Two mechanisms are proposed. The first one
involves the emergence of cells budding from the duct
epithelium, and expressing islet hormones, especially insulin [
These duct cells able to differentiate into ?-cells are called
?precursor cells.? According to a second mechanism, that has
been described only during the fetal life, the source of ?-cells
comes from a pool of proliferating cells expressing cytokeratin
(CK) and located near the ductal tree . Although it is
difficult to assess what is the respective contribution of each of these
mechanisms in the expansion of ?-cell during the fetal stage, it
is admitted that the first mechanism is the most current.
It is now well documented that neogenesis from ducts is
involved in the maintenance of the ?-cell mass and contributes to
its expansion in situations of increased insulin demand in adult
mammals including humans (reviewed in 9). Besides evident
limitations in the use of human tissue samples, the regulation of
?-cell differentiation in the adult stage is now better understood,
thanks to the use of animal models of pancreatic regeneration
and adaptation which stressed that ?-cell differentiation from
ductal cells can be strongly reactivated. Most importantly,
using specific models it is possible to recapitulate in the adult
situation, sequences found to occur during the development of
the endocrine pancreas i.e., a wave of ductal proliferation
followed by a subsequent differentiation of hyperplastic duct cells.
The main models are: transgenic mouse over-expressing INF?
], TGF? and gastrin over-expression [
], IL-6 or TNF?
], partial pancreatectomy ,
cellophane wrapping [
], main duct ligation [
], and chronic
glucose infusion in adult rats [
], which is a model of
pancreatic adaptation without initial injury of the pancreas. Using
the latest model, it was shown that 24 h of glucose infusion
were enough to double the ?-cell mass only by a stimulation of
the neogenic process, ?-cell proliferation being of minor
importance. It was also demonstrated that hyperinsulinemia and
hyperglycemia alone or in combination are able to dramatically
activate neogenesis and then increase the ?-cell mass, probably
through specific ways .
Although the different situations of pancreas remodeling
greatly contributed to the understanding of how ?-cells
differentiate in the adult situation, the question regarding the
presence and the location of true pancreatic stem cells in the adult
remains unanswered or, at least, largely controversial. For some
authors there is a pool of resting precursor cells inside ducts,
which has the ability to differentiate into ?-cell upon a specific
]. For other authors, all the ductal cells are
potentially precursors and are able to differentiate into ?-cells [
]. These cells are maintained in a quiescent status by presence
of TGF?, but proliferation and differentiation of these cells can
be reactivated upon the action of specific regulating factors as
described in Figure 2 [
]. Interesting recent observations by
Noguchi et al. [
] ascribe a particular role to the islet master
gene PDX-1 in ?-cell neogenesis from ductal cells. Indeed, the
authors showed that PDX-1 protein possesses a protein
transduction sequence in its structure, which allows it to permeate
cells. They also showed that transduced PDX-1 into culture of
pancreatic ducts triggered insulin gene expression. This
suggests that ductal PDX-1 expression can have paracrine effects
on (potentially progenitor?) neighboring cells within the
pancreatic duct and then may induce the first steps of ?-cell
differentiation. This is an attractive hypothesis, which needs however,
Currently there is no unique reliable method to directly
quantify the ductal-to ?-cell neogenesis. This is due to the
complexity of the mechanism, the involvement of many regulating
factors, and many cell intermediates, that are not universal but
may change according to the situation. The best way to
estimate the activation of ?-cell neogenesis from ducts is to evaluate
concomitantly key parameters such as: proliferation rate of
ductal cells, number of isolated ?-cells or ?-cell clusters budding
from ducts [
], number of ductal cells co-expressing several
pancreatic hormones [
], and finally the expression in the duct
cells of transcription factors involved in the differentiation of
Ductal Cell Precursors
The characterization of the ductal precursors has become
one of the major challenges for the upcoming research in ?-cell
differentiation. The phenotype of these precursors is difficult to
identify and it seems to be different between fetus and adult.
In the fetus, markers for these precursors are Glut-2, TrkA, and
vimentin when co-expressed with CK20 [
]. In the adult no
real marker for ductal cell precursors has been identified. In
fact a co-expression of CK20-Insulin or CK20-Glucagon has
been described in ductal cells, however these cells were already
in a late stage of differentiation, making this co-expression not
an early event of ductal-to ?-cell neogenesis. In any case, the
adult cell precursor and especially the ductal cell precursors are
very difficult to identify probably because of the heterogeneous
cell population that expressed different markers at the different
stage of the ?-cell differentiation [
Factors Regulating Neogenesis from Duct Epithelium
A large number of factors controlling the differentiation of
?-cells has been identified. Currently, these factors are
classified in the following main categories: growth factors (i.e.,
TGF?, TGF?, EGF, HGF, NGF, IGFs, and VEGF),
regeneration factors (i.e., INGAP, Reg), cytokine and inflammatory
factors (i.e., TNF?, IL-6, INF? ), and other hormones such as
PTHrP and GLP-1. It is obviously impossible to recapitulate
all these factors and their possible actions. Therefore, we
decided to concentrate here on GLP-1 because of the increasing
interest for this factor as a stimulator of ?-cell growth and its
potential use as a therapeutic agent in type 2 diabetes (detailed
information and references in Table 1).
GLP-1 and ?-Cell Growth
GLP-1 is an intestinal incretin hormone derived from the
processing of proglucagon, that exerts insulinotropic actions on
insulin-producing pancreatic islet ?-cells (reviewed in 29). The
importance of GLP-1 for stimulation of islet cell proliferation
was originally demonstrated in lean 20-day old normoglycemic
]. Afterwards, several studies using in vivo models
showed that GLP-1 can regulate islet growth mainly by
controlling ?-cell neogenesis [
]. Our own observations, using a
recognized model of ?-cells regeneration (neonatal Wistar rats
injected with streptozotocin, so-called n0-STZ), have shown
that GLP-1 and Exendin-4, applied during the neonatal period,
strongly stimulate ?-cell regeneration mainly by ?-cell
]. Furthermore, treatment of diabetic Goto-Kakizaki
(GK) rats with GLP-1 or Exendin-4 from day 2 to day 6 after
birth, resulted in stimulation of ?-cell neogenesis and
proliferation with persistent expansion of ?-cell mass detected at adult
]. Altogether these suggest that GLP-1 and its analogs
exert a major trophic role on pancreatic ?-cells, in addition to
theirs well-known effects on insulin biosynthesis and release.
The use of GLP-1 analogs gives for the first time the
possibility to pharmacologically stimulate ?-cells neogenesis from
precursor cells, even in diabetic adults.
GLP-1 and ?-Cell Differentiation from Cell Lines
Several studies have shown that incubation of
pancreatic exocrine cell lines with GLP-1 or Exendin-4 promotes
differentiation of these cells to an endocrine phenotype. AR42J
cells (rat pancreatic acinar cell line) treatment with GLP-1 or
Exendin-4 induces their differentiation into islet-like cells.
Differentiated cells exhibit increased expression of ?-cell genes
and the capacity to release insulin [
]. Similar experiments
were carried out using two pancreatic ductal cell lines, rat ARIP
and human PANC-1 cells [
]. Interestingly, the
differentiation of PANC-1 cells which are PDX-1 negative into
pancreatic ?-like cells after GLP-1 or Exendin-4 treatment required
transfection with human IDX-1 (PDX-1), whereas ARIP cells,
which are naturally PDX-1 positive, spontaneously
differentiated into insulin-secreting cells after GLP-1 exposure. Finally,
in Capan-1 cells derived from human pancreatic ductal
carcinoma, exposed to Exendin-4 during several days, the number
of cells containing insulin and glucagon increased to 10% from
40% in the basal state [
GLP-1 and ?-Cell Differentiation from Fetal and Adult
Several studies used fetal islet cell precursors to examine
whether exposure to GLP-1 or analogs is associated with
enhanced differentiation of previously immature islet precursors.
Thus, Exendin-4 has been shown to enhance PDX-1 expression
in human islet-like cell clusters treated for 4 days in vitro. After
transplantation of these cell clusters under the kidney capsule of
athymic rats, a 10-day treatment with exendin-4 induced
functional maturation of transplanted cells and growth of clusters,
as assessed 8 weeks following the transplant [
experiments showed that the treatment with GLP-1 can induce
differentiation and maturation of fetal pig islet clusters during culture.
Furthermore, transplantation of these in vitro treated cells into
immunodeficient mice revealed an enhanced insulin secretion
when exposed to glucose in vivo [
]. Recently, Abraham et al.
reported the expression of functional GLP-1 receptor into nestin
positive islet-derived progenitor cells (NIPs) and that GLP-1
stimulate the differentiation of NIPs into insulin-producing cells
In summary, a large amount of evidence suggest that
administration of GLP-1 or agonist promotes differentiation of
functional of ?-cells in vitro and vivo, thus strengthening the
possibility that GLP-1 and analogs may be useful for production
of new ?-cells and has important implications for the treatment
of type 1 and type 2 diabetes.
Transdifferentiation (Figure 3) was first defined as the
transforming process from a worm stage into an insect. Now the
use of this termination has been enlarged, and applied for lot of
organs in different species. One of the best examples is the
transdifferentiation from retinal cell epithelium into neuron in the
]. The relevance of this process for the generation of
new ?-cells remains somewhat controversial but recent studies,
that will be reported below, support this concept. According to
these studies, the cells which can potentially
?transdifferentiate? into ?-cells can belong to the pancreas, and even the islet,
itself or originate from extra-pancreatic tissues such as the liver.
Endocrine Cells into Duct Cells
Using a tri-dimensional cell culture system, Yuan et al. have
observed that isolated islet from post mortem patients were able
to transdifferentiate into ductal cells [
]. These ductal cells
presented particular properties since they still expressed enolase
which is a marker of the endocrine tissue. Moreover the authors
observed the appearance of the CK19 a marker of the fetal ductal
cell, suggesting that these cells were not fully mature but rather
corresponded to cells expressing an intermediate phenotype.
Endocrine Cells into Acinar Cells
Using the pancreatic duct ligation model, Bertilli et al. have
shown by electron microscopy and dual immunostaining the
presence of cells co-expressing insulin and amylase in both
endocrine and exocrine compartments [
]. Same results were
observed in transgenic mice overexpressing INF? [
presence of cells displaying both exocrine and endocrine
markers emphasizes the existence of an intermediate step during the
transdifferentiation process as found in experimental models of
pancreas remodeling that are associated with a strong ?-cell
neogenesis activity (reviewed in 3). Finally, human islets
maintained in vitro for a period of one year, could transdifferentiate
in some particular conditions. Endocrine cells can
transdifferentiate into exocrine cells and subsequently into an
undifferentiated phenotype characterized by the expression of enolase,
vimentin, CK7 and CK19, TGF? and EGFR. These
undifferentiated cells are considered by the authors as precursor cells
Acinar Cells into Duct Cells
Studies on the transdifferentiation of acinar cells into duct
cells were initially performed essentially for the understanding
of the earliest events that happened during the cancer of the
pancreas. The study of 7 pancreases from patients suffering
from chronic pancreatisis showed a cell transformation from
an acinar phenotype into a ductal phenotype, as assessed by the
reduction of the number of zymogene granules and the increase
of the size of the lumen of the future duct [
]. Similarly, data
from in vitro studies found that human adult acinar cells could
transdifferentiate into ductal cells when cultured on a collagen
]. Same results were observed by Hall et al. using
cultured human acinar cells [
], while Arias et al. described the
same phenomenon using other species such as rats and guinea
The AR42J Cell Model
AR42J is a cell line displaying acinar characteristics. These
cells are well known for their capacity to transdifferentiate into
different cell types when cultured in appropriate environment.
In the presence of activin A alone, they can turn into endocrine
phenotype expressing the pancreatic polypeptide, while in
presence of activin A and ?-cellulin, AR42J cells
transdifferentiate into insulin secreting cells [
]. Finally, in the presence of
GLP-1, AR42J cells can turn into insulin and glucagon
producing cells [
During embryonic development cells that have the ability
to transdifferentiate generally come from adjacent region. The
transdifferentiation from hepatic cells to pancreas cells is
probably one of the best documented [
] (Figure 3).
In 1986 Rao et al. observed the presence of
pancreaticlike tissue in the liver of rats when treated by polychlorinated
biphenyls, a carcinogenic agent. These cells organized in acini
as shown by location of the nucleus at the basal pole of the cells
and the presence of zymogen granules expressing amylase and
]. More recently, expression of pancreatic
enzymes (?-amylase, trypsinogen and lipase) was identified in
human liver during both development and maturation processes.
Using transgenic mice overexpressing INF? and treated with
KGF, Krakowski et al. observed the appearance of hepatocytes
and duct cells in pancreatic islets. Interestingly, these insular
duct cells displayed a high proliferative activity [
Hepatocyte Cell Precursors into Pancreatic Cells
Some cells of the liver Hering duct have the ability to
proliferate and to regenerate upon hepatic lesion. These cells also
called oval cells express some epithelial markers as CK19 and
hepatic markers as albumin. Moreover, these cells are
characterized by the expression on their plasma membranes of
antigen such as, c-kitR and Thy-1, which are also express in
hematopo??etic stem cells. These oval cells are able to
differentiate in vitro into epithelial biliary duct cells and into
hepatocytes. They are not considered as early cell precursors but
more likely as cell precursors dependent on regenerative
]. The most important characteristic of these oval
cells is that they are also found in pancreas in response to
specific stimuli. For example, in all models of
transdifferentiation from liver into pancreas, oval cells are found in
pancreas and more precisely in the ductal tree or adjacent to it [
Recently, Yang et al. showed that hepatic oval cells in culture
could differentiate into insulin secreting cells with most of the
characteristics of mature ?-cells. These cells could reverse
diabetes when injected into a diabetic rat [
]. Moreover, using
an approach based on flow cytometry Suzuki et al. were able to
isolate hepatic stem cells that retain the capacity to differentiate
into pancreatic cells .
Tsanadis et al. have shown inside human fetal pancreatic
islets the presence of a cell type morphologically different from
the commonly described endocrine and exocrine cell types [
These cells look as hepatocyte-like cells descending from the
ductal cell precursors observed in rat and hamster. The authors
conclude that these cells were a new population of cell
precursors inside human fetal islets. Fernandes et al. have described
using two animal models, (streptozotocin-injected and NOD
mice), the presence of intra-islets cell precursors. These
precursors co-expressing somatostatin and PDX-1 are able to
differentiate into ?-cells when the pancreas has undergone a
]. Recently Guz et al. have described two potential cell
precursors located inside islets using a model of pancreatic
]. The first precursor-type could express GLUT-2
as previously described by Pang et al. [
], while the second
could co-express somatostatin and insulin. Taken together these
studies strongly suggest the possibility of an activation of
neogenesis directly from precursor cells located inside islets. This
process could be considered as transdifferentiation of endocrine
non ?-cells into ?-cells.
Since a few years special attention was paid to intra-islet
nestin positive cells and for some authors nestin was considered
as a potential marker of precursor cells within the islet. Nestin
is an intermediate filament protein identified as a marker for
a multipotent stem cell population in the central nervous
]. Furthermore, nestin-expressing cells were reported
in pancreatic islets of adult mice [
], rats, and humans [
Clonigenicity and multipotency, including the capacity to form
new islet cells, were reported for nestin-positive cells from adult
] and fetal [
] pancreas. Knowing the role of nestin-positive
cells in central nervous system, nestin appeared as the ?ideal?
pancreatic precursor cells marker. However, nestin has also been
described as a marker for reactive stellate cells, or pericytes,
and endothelial cells during active angiogenesis [
authors reported that nestin is expressed in mesenchymal but not
epithelial cell precursors during development and is thus not
directly involved in islet neogenesis [
]. Therefore the role
of nestin-positive cells as endocrine pancreatic precursors
remains very controversial and the most recent data cast doubts as
to whether intra-islet nestin positive cells could be considered
as precursor cells in ?-cell neogenesis [
]. However, the
role of nestin positive cells in ?-cell neogenesis cannot be
totally excluded. Indeed, on the basis of an increasing amount of
67, 71, 73
], it can be proposed that nestin positive cells
indirectly may contribute to the generation of new endocrine
cells by promoting angiogenesis which in turn will promote
neogenesis by secreting trophic factors.
In conclusion, although different observations suggest the
presence of subpopulations of cell precursors inside islets of
Langerhans, it has been impossible so far to isolate precursor
cells from endocrine or ductal origins and the existence of such
cells must be considered with caution.
It has been long recognized that during late fetal and early
neonatal life, neogenesis is the main process which insures
?cell growth. There is now increasing evidence that the neogenic
process is also largely involved in ?-cell mass homeostasis in
the adult. Moreover, neogenesis appears as crucial for pancreas
plasticity, which is a unique property of the endocrine pancreas
to adapt the ?-cell mass to increased secretory demand without
hyperglycemia. This has been demonstrated repeatedly under
physiological (e.g., pregnancy, obesity) and pathological (e.g.,
growth hormone and cortisol excess) conditions [
experimental models of increased insulin demand (prolonged glucose
infusion) neogenesis is even the only process allowing ?-cell
The classical definition of endocrine cell neogenesis involves
the emergence of endocrine cells from undifferentiated
progenitor cells located in pancreatic ducts, which migrate into the
exocrine pancreas and proliferate to form the islets of
Langerhans. We attempted here to review some of the recent studies
in vivo and in vitro which prompt us to think that the generation
of new ?-cells may be not restricted to this process and rather
be the result of different mechanisms and require different
pancreatic and extra-pancreatic precursor cells. If pancreatic ducts
are the main source of precursor cells, it is unlikely that there
is a unique precursor and, for the moment, a specific marker
of these precursor cells is still lacking. The possible ability of
PDX-1 to induce insulin gene expression in pancreatic ducts
by a paracrine effect is a very interesting hypothesis, which
deserves further studies.
If the search of intra-islet precursors is somewhat
disappointing for the moment, the possibility of an activation of neogenesis
directly from precursor cells located inside islets is supported by
some studies [
]. Especially, the conversion of endocrine
non ?-cells into ?-cells [61; Paris et al., personal
communication] is a new way to explore. In addition, although nestin
positive cells are very probably not intra-islet precursors of ?-cells,
the studies on these cells opened a new research field, i.e., the
relationship between ?-cell neogenesis and angiogenesis [
Finally, to take advantage of the transdifferentiation
process, especially the transdifferentiation from acinar cells, as a
mechanism to obtain a source of differentiated ?-cells may be a
direction for future cellular therapies. Acinar tissue in pancreas
represents more than 95% of the mass of the organ and may be
considered as a potential source of ?-cell.
Ultimately, a better understanding of the molecular
mechanisms involved in ?-cell neogenesis will allow us to use any type
of differentiated [
] and/or undifferentiated cells as a source
of potential cell precursors.
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