Cellular stress drives pancreatic plasticity

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Science Translational Medicine  04 Feb 2015:
Vol. 7, Issue 273, pp. 273ps2
DOI: 10.1126/scitranslmed.3010577


Controversy has long surrounded research on pancreatic beta cell regeneration. Some groups have used nonphysiological experimental methodologies to build support for the existence of pancreatic progenitor cells within the adult pancreas that constantly replenish the beta cell pool; others argue strongly against this mode of regeneration. Recent research has reinvigorated enthusiasm for the harnessing of pancreatic plasticity for therapeutic application—for example, the transdifferentiation of human pancreatic exocrine cells into insulin-secreting beta-like cells in vitro; the conversion of mouse pancreatic acinar cells to beta-like cells in vivo via cytokine treatment; and the potential redifferentiation of dedifferentiated mouse beta cells in vivo. Here, we highlight key findings in this provocative field and provide a perspective on possible exploitation of human pancreatic plasticity for therapeutic beta cell regeneration.

A metabolic disorder, diabetes occurs because of inadequate insulin production by the pancreatic beta cells coupled with a poor response to insulin by muscle, fat, and liver cells (termed insulin resistance). Although insulin therapy and diabetes medications are adequate to regulate glucose homeostasis, the quality of life for some diabetes patients remains low as a result of life-endangering hypoglycemic episodes and multi-organ complications (e.g., eyes, vascular system, kidneys, and nervous system). Therefore, current translational efforts in the regenerative medicine arena focus on cell replacement therapies for the replenishment of insulin-producing beta cells. Some of these strategies involve the generation of beta cells from pluripotent stem cells and endogenous endodermal derivatives such as hepatocytes and gastrointestinal, pancreatic ductal, acinar, or other endocrine cells (1).

The existence of a “pancreatic stem cell” remains elusive, but pancreatic plasticity—that is, transdifferentiation from one pancreatic cell type to another—such as evidence of insulin-producing beta-like cells within exocrine tissue (acinar and ductal cells) has gained considerable attention. Early experiments carried out by Bonner-Weir and Heimberg suggest some form of pancreatic plasticity and an intrinsic ability of the adult pancreas to regenerate (see Table 1). These studies demonstrate that beta cells can be restored in times of need, such as during injury and cellular stress. More recently, a wave of literature uncovering the potential of exocrine and endocrine cells to transdifferentiate and regenerate pancreatic beta cells, both in vitro and in vivo, has emerged. Furthermore, work by several groups has brought to light the phenomenon of beta cell dedifferentiation under physiological and pathophysiological states.

Table 1

Pancreatic plasticity: Summary of literature.

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From a clinical point of view, these findings underscore the inherent plasticity of the pancreas and suggest the possibility of stimulating endogenous beta cell neogenesis or regeneration in vivo without the need for invasive methodologies. Here, we briefly summarize the literature and present a perspective on how plasticity associated with human pancreatic exocrine and endocrine cells, despite existing controversies, might potentially be harnessed for the regeneration of the beta cells in diabetic patients.


Nonphysiological stresses. The concept of intrapancreatic cell-to-cell conversion, particularly under states of injury or cellular stress, is not new. Research on pancreatic duct ligation (PDL) and partial pancreatectomy (PPx) has been carried out since the 1600s, but evidence of acinar and ductal cell differentiation toward islet cell phenotypes in these pancreatic injury models began to emerge in the first decade of the 1900s (2). More recently, cell lineage–tracing experiments demonstrated that, after birth and after PDL injury, carbonic anhydrase II (CAII)–expressing ductal epithelial cells in the pancreas give rise to new acinar tissue (clusters of exocrine pancreas cells that synthesize, store, and secrete digestive enzymes) and islets of Langerhans (which contains, alpha, beta, delta, PP, and epsilon cells) (3). In addition, Heimberg and colleagues demonstrated that in response to PDL, cells in the ductal lining of the mouse exocrine pancreas can be converted into endocrine progenitors guided by the expression of neurogenin 3 (Ngn3), a key transcription factor for endocrine pancreas specification (4). These Ngn3+ progenitor cells can subsequently contribute to beta cell neogenesis and proliferation, leading to the doubling of beta cell volume. Importantly, a selective knock out (KO) of Ngn3 in preexisting beta cells does not ablate this effect, suggesting that beta cell neogenesis occurs from non-beta cells (5).

Lineage tracing of exocrine acinar–to–endocrine cell transdifferentiation after PDL in rodents was first reported by Pan et al. (6). After PDL and elimination of pre-existing beta cells via treatment with streptozotocin (STZ, a chemical of microbial origin that is toxic to beta cells and used to create rodent diabetes models), the authors lineage-traced pancreas-specific transcription factor 1a (Ptf1a)–expressing acinar cells and showed that these cells give rise to endocrine beta cells via Ck19+/Hnf1β+/Sox9+ ductal and Ngn3+ endocrine pancreas progenitor intermediates in vivo. Acinar cell dedifferentiation into a progenitor-stage pancreatic cell (Pdx1+Ecadherin+Beta-catenin+) after chemically (caerulein, an oligopeptide that causes pancreatitis)–induced pancreatic injury in vivo has also been reported (7).

Collectively, these nonphysiological models demonstrate that exocrine cells in rodents, upon severe injury, prompt beta cell regeneration via transdifferentiation mechanisms (Fig. 1). Human pancreatic exocrine cells (ductal cells) were successfully converted into beta-like cells recently, presenting a potential translational opportunity for human beta cell replacement (8, 9).

Fig. 1 Intrapancreatic cell conversions.

Shown is a schematic representation of pancreatic plasticity induced by various stressors. Stress induced by cytokines, nutrients, injury, and other physiological stressors has been implicated in the induction of intrapancreatic cell-to-cell conversion. The inherent plasticity of the pancreas is promising for regenerative medicine, as beta cell regeneration is a major goal for future diabetes therapies. IL-22, interleukin 22; RANTES, regulated on activation, normal T cell expressed and secreted [also known as CCL5, chemokine (C-C motif) ligand 5].


Physiological stresses: Cytokines and nutrients. Multiple lines of evidence suggest that cytokine- and nutrient-induced physiological stresses also can promote exocrine cell–to–beta cell transdifferentiation (Table 1). Glucose challenge experiments performed by Lipsett and Finegood in rats indirectly suggested that acinar cells transdifferentiate into beta cells (10). In zebrafish, high nutrient concentrations can also promote ductal cell–to–beta cell transdifferentiation (11). The ability of cytokines to promote exocrine cell–to–beta cell transdifferentiation as well as beta cell neogenesis has also been reported. In 1993, Gu and Sarvetnick first demonstrated that transgenic mice overexpressing interferon γ (IFN-γ) in pancreatic beta cells displayed proliferation and differentiation of pancreatic ductal cells into endocrine cells (12). After a hiatus of two decades, another cytokine, tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), was shown to stimulate ductal cell proliferation and transient expression of Ngn3, ultimately giving rise to new pancreatic beta cells (13). More recently, Baeyens et al. demonstrated that transient epidermal growth factor (EGF) and ciliary neurotrophic factor (CNTF) treatment stimulates Ngn3 expression in acinar cells, which subsequently transdifferentiated into beta cells and restored euglycemia in diabetic mice (14).

Taken together, these experiments in model organisms highlight the plastic nature of the pancreas and suggest that it favors beta cell regeneration in states of stress. Notably, the fact that transient exposure to cytokines promotes acinar cell–to–beta cell transdifferentiation in mice (14) means that it might be possible to use such an intervention to regenerate human pancreatic beta cells in vivo (Fig. 1). This is of high clinical and translational relevance because diabetic patients are typically exposed to inflammatory cytokines and prolonged low-grade inflammation. This means that the appropriate use of the correct cytokines may eventually serve to restore pancreatic beta cell function (15).


Although the evidence highlighted above suggests the presence of beta cell progenitors within adult exocrine cells, there are also numerous opposing studies indicating that this is not the mechanism by which adult beta cells regenerate (at least in rodents). In pancreatic injury models such as PPx (16) and diphtheria toxin–based beta cell depletion (17), it was found that new beta cells arise predominantly from proliferation of preexisting beta cells during adult life. Subsequent studies proposed that pancreatic ductal cells give rise to beta cells during pancreatic embryogenesis but not after birth following experimentally induced injury models such as PDL (18) and alloxan-induced beta cell ablation (19). Using lineage-tracing studies in various models of beta cell loss, Xiao et al. did not find evidence of beta cell neogenesis in adult mice despite an up-regulation of Ngn3 in proliferating duct cells and in preexisting beta cells (20). Rankin et al. performed PDL and comprehensive whole pancreas beta cell quantification to conclude that no progenitors contribute to beta cell mass regeneration. Accordingly, PDL stimulates excessive pancreatic injury, thereby affecting the way by which beta cell content can be accurately measured (21).

Despite this intensive debate on the presence or absence of rodent beta cell progenitors that can regenerate the adult pancreas, transdifferentiation of cells from one type to another is now generally accepted as a possibility. In a recent Perspective, Van de Casteele et al. discussed the work by various laboratories in an attempt to explain the discrepancies that exist in the field of injury (PDL)–induced beta cell regeneration (22).


Nonphysiological stresses: Chemically induced beta cell death and PDL. Given the abundance of pancreatic exocrine versus endocrine tissue, it is not surprising that there has been a huge focus on exocrine cell transdifferentiation for regenerative medicine purposes. Many groups have performed excellent work to demonstrate that pancreatic alpha cells can actually transdifferentiate into beta cells—a degree of pancreatic plasticity that had been neglected (Fig. 1 and Table 1). Using nonphysiological models, breakthrough work by Thorel et al. demonstrated that diphtheria toxin–induced beta cell depletion can promote alpha cell–to–beta cell transdifferentiation (23). Subsequently, Chung et al. combined PDL with high-dose alloxan (a chemical that destroys beta cells) in mice to demonstrate that, in adult animals, new beta cells are primarily derived from alpha cells (24). More recently, the same group showed that transdifferentiation of alpha–to–beta–to–delta cells could be observed in mice (in vivo) following caerulein treatment and in human type 1 diabetic pancreatic sections (ex vivo) (25). On the basis of their findings, the authors proposed that autoimmunity plays a role in islet-cell interconversion, which has enormous implications for the treatment of human type 1 diabetes (25).

Physiological stress. Physiological stresses such as insulin resistance, chronic hyperglycemia, multiparity, aging, and oxidative stress also have been implicated in epigenetic actions that alter islet cell mass and interconversions (26). The comparison of insulin-resistant versus insulin-sensitive human pancreatic samples by Mezza et al. suggests that insulin resistance is linked to alpha (and ductal) cell–to–beta cell transdifferentiation in human type 2 diabetes patients (27). In addition, beta cell plasticity in states of physiological stress has also been reported. In 1999, Jonas et al. demonstrated that PPx-induced hyperglycemia is marked by beta cell dysfunction and a loss of mature beta cell gene expression (28). More recently, Talchai et al. reinvigorated the concept of beta cell plasticity by demonstrating that physiological stresses such as chronic hyperglycemia, multiparity, and aging induce beta cell dysfunction and dedifferentiation (29). The dedifferentiated beta cells reexpress Ngn3, and some of the cells revert to alpha cells. These results were subsequently confirmed in other mouse models of metabolic stress (29). Remarkably, dedifferentiated Ngn3+Ins- cells can be redifferentiated into mature Ngn3-Ins+ beta cells after insulin therapy, raising hopes that the loss of beta cell function in humans might be reversible (30). Another recent study indicates that, in islets from human type 2 diabetes patients, oxidative stress–associated beta cell dysfunction induces cytoplasmic translocation and inactivation of MAFA, NKX6.1, and PDX1, all of which are mature beta cell transcription factors (31). Collectively, these studies indicate that beta cell “dysfunction” may be a reflection of stress-induced beta cell dedifferentiation.

From a translational medicine standpoint, the ability to (i) halt the dedifferentiation process of beta cells, (ii) redifferentiate these stress-derived beta cell “progenitors,” and (iii) facilitate alpha cell–to–beta cell conversion would allow potential repopulation of the functional beta cell pool in diabetic patients.


A common theme within the field of pancreatic plasticity—mechanisms of trans- or dedifferentiation—is focused on the re-emergence of Ngn3 expression in terminally differentiated adult cells. Ngn3 is a transcription factor and master regulator that determines pancreatic endocrine cell fate during embryogenesis, but researchers are currently debating its importance in beta cell neogenesis. Some studies indicate that injury by PDL does not result in Ngn3 up-regulation, whereas others suggest that activation of Ngn3 does occur but without resulting in beta cell neogenesis (20, 22). Conversely, there are also studies that show that overexpression of Ngn3 in mouse and rat pancreatic duct epithelial cells is sufficient to induce endocrine cell fate (32). Work by Johansson et al. has shown that the temporal increment of Ngn3 expression promotes pancreatic progenitors to differentiate into distinct endocrine cell types in mice (33), but the expression pattern of Ngn3 in the mouse is distinctly different from that in humans (34). Importantly, Ngn3 is also purportedly expressed in the adult pancreas, whereby it is essential for the expression of beta cell genes that encode NeuroD1, Pax4, MafA (pancreatic developmental transcription factors), and insulin (35). Further investigations are warranted to determine the significance of reemergence of Ngn3 expression in these transdifferentiation observations. Speculatively, should the Ngn3 expression result in increased alpha cell formation, as suggested by Talchai et al. (29), the increased glucagon and glucagon-like peptide 1 (GLP-1) secreted by the new alpha cells might promote beta cell formation (36). Furthermore, it may be worthwhile to ectopically stimulate Ngn3 expression should it eventually be determined to be critical for the transdifferentiation of human exocrine or alpha cells to beta cells.


Ample evidence indicates that the pancreas possesses the plasticity that allows it to regenerate under various states of stress. However, several challenges remain. First, misappropriated plasticity might be a threat, as inflammatory stress can lead to pancreatitis—a major risk factor for developing pancreatic adenocarcinoma (37). It is important to recognize that embryonic pathways, such as NOTCH signaling, that play a role in acinar regeneration during pancreatic development have also been linked to neoplastic transformation (37). The second challenge relates to understanding and controlling how stress mechanisms can be used to induce the desired cell type. For example, during states of metabolic stress, Talchai et al. demonstrated that dedifferentiated beta cells are able to redifferentiate, albeit adopting an alpha cell fate instead (29). Furthermore, the finding that Ngn3+ progenitors observed in diabetic mice can redifferentiate into insulin+ cells upon insulin therapy is critical, because it suggests that the presence of cellular stress might also hinder the redifferentiation of these progenitors into mature beta cells (30). In conclusion, stress-induced pancreatic plasticity is a controversial area of research on a process that still is not fully understood. Nevertheless, there is great promise that unraveling its intricate mechanisms will allow us to translate these findings into therapies that contribute to pancreatic regenerative medicine.

References and Notes

Acknowledgments: We thank H. M. Guajardo and K. Gonzalez for their review of this manuscript. Funding: I.A.V. is supported by a U.S. National Institutes of Health (NIH) F31DK098931 award. A.K.K.T. is supported by Juvenile Diabetes Research Foundation postdoctoral fellowship 3-2013-236 and currently by the Institute of Molecular and Cell Biology (IMCB), A*STAR. R.N.K. is supported by HSCI award SG-0078-12-00; NIH grants RO1 DK 67536, RO1 DK 103215, and RO1 DK 055523; and a grant from AstraZeneca. Competing interests: The authors declare that they have no competing interests.

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