Stress‐induced adaptive islet cell identity changes

Abstract

The different forms of diabetes mellitus differ in their pathogenesis but, ultimately, they are all characterized by progressive islet β-cell loss. Restoring the β-cell mass is therefore a major goal for future therapeutic approaches. The number of β-cells found at birth is determined by proliferation and differentiation of pancreatic progenitor cells, and it has been considered to remain mostly unchanged throughout adult life. Recent studies in mice have revealed an unexpected plasticity in islet endocrine cells in response to stress; under certain conditions, islet non-β-cells have the potential to reprogram into insulin producers, thus contributing to restore the β-cell mass. Here, we discuss the latest findings on pancreas and islet cell plasticity upon physiological, pathological and experimental conditions of stress. Understanding the mechanisms involved in cell reprogramming in these models will allow the development of new strategies for the treatment of diabetes, by exploiting the intrinsic regeneration capacity of the pancreas.

β Cells led astray by transcription factors and the company they keep

“…In this issue, studies from the laboratories of Sussel (8), Dor (9), and Stoffers (10) collectively reinforce the consensus view that the same TFs that direct β cell specification are also required to maintain the gene activation and repression programs that undergird mature β cell identity (11)(12)(13)(14)(15). This unexpected property of the murine and human β cell transcriptional network provides an additional explanation for the intrinsic fragility, sensitivity (16), and propensity of these cells to adopt alternate endocrine cell fates as a consequence of various stressors (2,4,17). Importantly, these studies probe the different relationships of NKX2.2, PAX6, and the LIM domainbinding protein 1-islet 1 (LDB1-ISL1) complex to the chromatin modification machinery in adult β cells and show how the expression and function of these TFs are sensitive to environmental and metabolic changes associated with T2D.…”

“…This mechanism may lend itself to the ability to rapidly adapt to changes in homeostasis at the transcriptional level, as is necessary for professional, nondividing secretory MAFA, FOXO1, and NKX6.1, are vulnerable to dysregulation in T2D due to metabolic stressors, such as chronic hyperglycemia and oxidative damage (1,3,6). These observations dovetail nicely with the intrinsic fragility of mature β cells when challenged with various stressors (4,16) and suggest that the sensitivity of these core β cell TFs to stress is an explanation for β cell fragility. The studies on PAX6 and LDB1 indicate that they too fall into this category.…”

“…β Cell plasticity A growing body of evidence from studies in mice and humans indicates that dedifferentiation or partial transdifferentiation/reprogramming of β cells into alternate endocrine cell fates can alter glucose homeostasis (1)(2)(3)(4)(5). β Cell dedifferentiation is generally characterized by the loss of insulin content and gene expression, as well as decreased expression of genes encoding β cell-specific transcription factors (TFs), such as NK6 homeobox 1 (NKX6.1), pancreatic and duodenal homeobox 1 (PDX1), forkhead box protein O1 (FOXO1), neuronal differentiation 1 (NEUROD1), and MAF bZIP transcription factor A (MAFA) (6), and reactivation of endocrine progenitor cell markers such as neurogenin 3 (NGN3) (4,7).…”

“…β Cell dedifferentiation is generally characterized by the loss of insulin content and gene expression, as well as decreased expression of genes encoding β cell-specific transcription factors (TFs), such as NK6 homeobox 1 (NKX6.1), pancreatic and duodenal homeobox 1 (PDX1), forkhead box protein O1 (FOXO1), neuronal differentiation 1 (NEUROD1), and MAF bZIP transcription factor A (MAFA) (6), and reactivation of endocrine progenitor cell markers such as neurogenin 3 (NGN3) (4,7). Similarly, adult β cells can also become transdifferentiated or partially reprogrammed to adopt alternate islet cell properties, such as the capacity for glucagon and/or somatostatin production, accompanied by defects in the expression or regulation of β cell TFs as well (4,5). An understanding of the mechanisms that drive β cell dedifferentiation and partial transdifferentiation into α, pancreatic polypeptide (PP), or δ cell fates in response to various insults is only beginning to emerge.…”

Evidence for Loss in Identity, De-Differentiation, and Trans-Differentiation of Islet β-Cells in Type 2 Diabetes

“…The past decade has revealed in numerous rodent models that various stressors can impart pancreatic cell reprogramming, although it has been argued that β-cell replacement by replication is the predominant mechanism (Dor et al, 2004; Teta et al, 2007). Some physiological stressors, including pregnancy or obesity, have not provided clear evidence of islet cell reprogramming (reviewed in Cigliola et al, 2016). However, it appears that extreme physical injury, chemical stresses, or genetic perturbations are able to promote reprogramming (Figure 2).…”