ReviewReprogramming into pancreatic endocrine cells based on developmental cues
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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Temporal analysis of distribution pattern of islet cells and antioxidant enzymes for diabetes onset in postnatal critical development window in rats
2019, Life SciencesCitation Excerpt :Pancreatic islets are specialized endocrine micro-organs composed of cells alpha α (glucagon), beta β (insulin), delta δ (somatostatin), PP (pancreatic polypeptide), and epsilon Ɛ (ghrelin) [1].
NKX6.1 induced pluripotent stem cell reporter lines for isolation and analysis of functionally relevant neuronal and pancreas populations
2018, Stem Cell ResearchCitation Excerpt :Interestingly, expression of SST was observed both in the NKX6.1 positive and negative populations and we confirmed the expression of somatostatin in both GFP-positive and negative cells by both flow cytometry and immunofluorescence imaging. Previous studies focusing on mouse pancreas development have suggested a bifurcation during endocrine development, with cells being directed towards either an alpha/PP or delta/beta progenitor cell before resolving into mature endocrine cells (Sosa-Pineda et al., 1997; Collombat et al., 2003; Kordowich et al., 2010). Our observations suggest that during development of human delta cells, these cells could arise from a progenitor cell expressing both somatostatin and NKX6.1.
The influence of matrix properties on growth and morphogenesis ofhuman pancreatic ductal epithelial cells in 3D
2013, BiomaterialsCitation Excerpt :Currently, the studies of PDEC in 3D are mostly relying on biologically-derived matrices that not only have undefined and batch-dependent biochemical compositions but also have very limited tunability in gel biophysical properties such as stiffness and molecular transport. In addition to being used as a cell model for PDAC studies, pancreatic exocrine cells, such as PANC-1, are increasingly used in efforts related to endocrine differentiation [10–15]. PANC-1 cells can be trans-differentiated into insulin-secreting cell clusters under serum deprivation and with the use of appropriate soluble cues such as glucagon-like peptide 1 (GLP-1) [10,11], FGF2 [12], and stem cell factor (SCF) [13].
Generating insulin-producing cells for diabetic therapy: Existing strategies and new development
2013, Ageing Research ReviewsCitation Excerpt :Subsequently, endocrine subtype lineages are progressively specified by the activation of a complex network of transcription factors (Collombat et al., 2006). For example, Arx promotes the fate of α-/PP-cells, whereas Pax4 induces β-/δ-cell lineages (Kordowich et al., 2010). Thus, these endocrine cells would be more easily transformed into each other.
The pancreatic islet: What we know 150 years after Langerhans
2019, Bulletin de l'Academie Nationale de MedecineStem cells in the treatment of insulin-dependent diabetes mellitus
2016, Acta Naturae