Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx

Abstract

Summary Insulin-producing pancreatic β-cells in mice can slowly regenerate from glucagon-producing α-cells in settings like β-cell loss, but the basis of this conversion is unknown. Moreover it remains unclear if this intra-islet cell conversion is relevant to diseases like type 1 diabetes (T1D). We show that the α-cell regulators Aristaless-related homeobox (Arx) and DNA methyltransferase 1 (Dnmt1) maintain α-cell identity in mice. Within 3 months of Dnmt1 and Arx loss, lineage tracing and single cell RNA sequencing revealed extensive α-cell conversion into progeny resembling native β-cells. Physiological studies demonstrated that converted α-cells acquire hallmark β-cell electrophysiology, and show glucose-stimulated insulin secretion. In T1D patients, subsets of Glucagon-expressing cells show loss of DNMT1 and ARX, and produce Insulin and other β-cell factors, suggesting that DNMT1 and ARX maintain α-cell identity in humans. Our work reveals pathways regulated by Arx and Dnmt1 sufficient for achieving targeted generation of β-cells from adult pancreatic α-cells.

A Chromatin Basis for Cell Lineage and Disease Risk in the Human Pancreas

“…While the molecular mechanisms of pancreatic cell fate conversion are not entirely understood, evidence in other systems point to chromatin structure as a major determinant of successful reprogramming outcome (Soufi et al, 2012; Xu et al, 2011). Supporting this view, loss of chromatin regulators like DNA methyltransferases has been shown to promote islet cell type interconversion (Chakravarthy et al 2017; Dhawan et al, 2011). To examine the potential for cell fate conversion at the chromatin level in α-, β-, duct or acinar cells, we calculated the correlation between the DOR clusters based on the genes that are assigned by the GREAT algorithm (Figure 5A, Table S6).…”

“…Recent mouse studies have revealed conditions, like extreme β-cell loss or genetic loss-of-function, that promote conversion of pancreatic endocrine cells into β-cells (Chakravarthy et al, 2017; Chera et al, 2014; Thorel et al, 2010) or into a-cells (Dhawan et al, 2011). In mice and humans, adult exocrine cells can also be reprogrammed into insulin-producing cells resembling β-cells (Lee et al, 2013; Zhou et al, 2008).…”

“…A growing consensus is that this effort could benefit from improved understanding of the gene regulatory mechanisms governing native human islet cell fate, diversification and function. Recent studies in mice suggest that endocrine cells like pancreatic a-cells or δ-cells can interconvert toward a β-cell fate, after profound β-cell destruction or genetic loss-of-function (Chakravarthy et al, 2017; Chera et al, 2014; Thorel et al, 2010). Similarly, exocrine ductal or acinar cells have been shown to interconvert toward a ß-cell fate after genetic gain- or loss-of-function (Lee et al, 2013; Zhou et al, 2008) or cytokine exposure (Baeyens et al, 2013).…”

“…Thus, pancreatic cell transdifferentiation has emerged as another possible means for generating replacement islet cells. Findings from prior studies using rodent models suggest that cell interconversion is governed and can be manipulated through epigenetic mechanisms (Chakravarthy et al, 2017; Dhawan et al, 2011). Harnessing the therapeutic potential of native pancreatic cells could benefit from improved characterization of the transcriptomes, epigenomes and the chromatin landscape of native pancreatic cells in development or disease.…”

Gcg CreERT2 knockin mice as a tool for genetic manipulation in pancreatic alpha cells

“…However, it has become evident that dysregulation of glucagon secretion by alpha cells also contributes to diabetes development and severity, indicating that alpha cells could also be a therapeutic target for better management of the disease [1, 2]. In addition, recent studies have suggested that alpha cells might be a potential source for the generation of new beta cells to cure diabetes [3–5]. …”