Review
Reprogramming into pancreatic endocrine cells based on developmental cues

https://doi.org/10.1016/j.mce.2009.12.016Get rights and content

Abstract

Due to the increasing prevalence of type 1 diabetes and the complications arising from actual therapies, alternative treatments need to be established. In order to compensate the beta-cell deficiency associated with type 1 diabetes, current researches focus on new strategies to generate insulin-producing beta cells for transplantation purpose, including the differentiation of stem or progenitor cells, as well as the transdifferentiation of dispensable mature cell types. However, to successfully force any cell to adopt a functional beta-cell fate or phenotype, a better understanding of the molecular mechanisms underlying the genesis of these in vivo is required. The present short review summarizes the hitherto known functions and interplays of several key factors involved in the differentiation of the endocrine cell lineages during pancreas morphogenesis, as well as there potential in generating beta cells. Furthermore, an emphasize is made on beta-cell regeneration and the determinants implicated.

Introduction

Over the past decades, diabetes became one of the most widespread metabolic disorders with epidemic dimension affecting almost 6% of the world's population. By the year 2025, the number of person affected by type 1 or 2 diabetes is projected to reach 300 millions. For instance, in Asia, where a fast change in lifestyle and dietary habits is occurring, the number of diabetic patients is increasing faster than anywhere else. Herein, we will focus on type 1 diabetes, which is characterized by a selective loss of insulin-producing beta cells in the endocrine pancreas as a result of an autoimmune reaction. Left untreated, the induced shortage in insulin hormone may lead to complications, such as micro- and macro-vascular damages, blindness, amputation and/or death. Current treatments involve daily injections of exogenous insulin in order to compensate the deficiency in this hormone. However, environmental factors, such as exercise, diet, or age, may cause marked variations in blood glucose levels despite insulin therapy and eventually lead to the complications discussed previously. Islet transplantation represents a substitute to insulin therapy, but the shortage in donors prevents its widespread use. Thus, other alternatives must be found in order to efficiently treat the consequences of type 1, but also type 2, diabetes, both diseases eventually resulting in loss and/or insufficient numbers of beta cells.

In this context, the generation of pancreatic beta cells from stem, progenitor or other cell subtypes may represent an interesting option. However, to design rational protocols allowing the in vitro or in vivo generation of beta cells, it is imperative to gain further insight into the molecular determinants controlling the development of embryonic, but also adult beta cells, in vivo.

Section snippets

Formation of the developing pancreas

The pancreas plays a crucial role in nutritional homeostasis through synthesis and secretion of hormones and enzymes. This organ includes three tissue types: acinar, ductal and endocrine. The exocrine pancreas consists of acinar cells secreting digestive enzymes, such as amylases, lipases, proteases and nucleases, which are emptied into the pancreatic duct forming an elaborately branched network of tubules composed of epithelial duct cells. The latter produce bicarbonate ions and electrolytes,

The genetic program underlying the genesis of the pancreas

In the following, we outline some of the most crucial key players (Pdx1, Ngn3, IA1, Pax4, Arx, Nkx2.2, Nkx6.1, Nkx6.2, Pax6, MafA) implicated in the specification of the pancreatic cell subtypes with particular emphasis on the endocrine lineages.

Pdx1, a homedomain-containing transcription factor, is expressed as early as E8.5 in the dorsal and ventral endoderm distal to the stomach and duodenal epithelium. Subsequently, Pdx1 expression progressively becomes restricted to the beta-cell lineage

Reprogramming into pancreatic cells

In the last years, several studies outlined an unsuspected plasticity of mature pancreatic cells (Tosh and Slack, 2002, Eberhard and Tosh, 2008). Such findings opened new avenues for the treatment of type 1 diabetes as some of them established that particular pancreatic cell types may be forced to adopt an alternate phenotype through the misexpression of selected transcription factors. The analysis of the genetic determinants underlying the genesis of the different cell subtypes and the

Mechanisms of beta-cell replenishment in vivo

Among the several approaches envisaged to treat diabetes-related beta-cell insufficiency, the in vivo regeneration of insulin-producing beta cells appears of great potential. The fact that the adult beta-cell mass is not static, but fluctuates in response to changing physiological conditions, such as pregnancy and insulin-resistance, outlines the activity of adaptive mechanisms (Lingohr et al., 2002, Bonner-Weir, 2000). Furthermore, several approaches, including surgical ablation of pancreatic

Conclusions and future aspects

An active research aiming at characterizing the mechanisms underlying normal and pathological pancreas development uncovered numerous key factors and allowed the elucidation of some of their mutual interactions. This knowledge was/is used as a roadmap for the directed in vivo and in vitro generation of functional beta cells and raises hopes for a suitable beta-cell replacement-therapy in order to improve type 1, but also type 2, diabetes treatment. However, despite these promising progresses,

Acknowledgements

The authors are supported by the Max-Planck Society, the Dr. H. Storz and Alte Leipziger foundation, the Juvenile Diabetes Research Foundation (26-2008-639), the INSERM AVENIR program, the INSERM, and the NIH Beta Cell Biology Consortium (U19 DK 072495-01).

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