Replication confers β cell immaturity

Abstract

Pancreatic β cells are highly specialized to regulate systemic glucose levels by secreting insulin. In adults, increase in β-cell mass is limited due to brakes on cell replication. In contrast, proliferation is robust in neonatal β cells that are functionally immature as defined by a lower set point for glucose-stimulated insulin secretion. Here we show that β-cell proliferation and immaturity are linked by tuning expression of physiologically relevant, non-oncogenic levels of c-Myc. Adult β cells induced to replicate adopt gene expression and metabolic profiles resembling those of immature neonatal β that proliferate readily. We directly demonstrate that priming insulin-producing cells to enter the cell cycle promotes a functionally immature phenotype. We suggest that there exists a balance between mature functionality and the ability to expand, as the phenotypic state of the β cell reverts to a less functional one in response to proliferative cues.

Single cell transcriptome profiling of mouse and hESC-derived pancreatic progenitors

“…Previously studies in adult b-cells suggest proliferation is accompanied by a 233 decrease in the function and maturation of b-cells (30,31). To understand if a similar 234 process occurs during mouse b-cell development, we profiled the expression of several 235 b-cell maturity and progenitor markers in the b1, b2, S and M phase populations of cells 236…”

Tead1 reciprocally regulates adult β-cell proliferation and function to maintain glucose homeostasis

“…A loss of function of these genes is associated with a loss of mature function accompanied by a fetal/immature gene expression phenotype with expression of disallowed genes with high MafB expression and loss of MafA expression. In contrast to this de-differentiation phenotype, that is seen in many adult β-cell proliferative phenotypes, such as with activation of c-Myc (Puri et al, 2018) or Notch (Bartolome et al, 2019), loss of Tead1 function is not associated with re-expression of many of the disallowed genes, such as Ldha, nor a re-expression of MafB, markers of immature mouse β-cells (Nishimura et al, 2006). Interestingly a change in methylation status of the promoters of the genes has been associated with acquisition of mature β-cell function, specifically demethylation of the promoters of genes associated with maintenance of mature β-cell function and methylation of disallowed gene promoters (Dhawan et al, 2015).…”

“…Acquisition of mature function is often accompanied by proliferative quiescence in many cell types, including β-cells (Puri et al, 2018). The molecular mechanisms underlying this reciprocal regulation has been poorly understood and this knowledge gap limits many therapeutic approaches in regenerative medicine.…”

“…In type 1 diabetes, there is an autoimmune destruction of insulin-producing β-cells, while in type 2 diabetes (T2D) there is, often, significant insulin resistance with varying degrees of β-cell dysfunction, accompanied by a reduction in β-cell mass (Butler et al, 2003) . Current strategies to promote proliferative capacity in adult β-cells are limited by concurrent loss of mature function (Bensellam et al, 2018;Efrat, 2008;Puri et al, 2018). Hence, understanding the interacting mechanisms regulating maintenance of functional competence, proliferation, and quiescence in adult β-cells is critical to enhancing functional βcell mass.…”

Establishing cell-intrinsic limitations in cell cycle progression controls graft growth and promotes differentiation of pancreatic endocrine cells

“…Overexpression of the pro-proliferation molecules cyclin-dependent kinases in primary rat beta cells increases proliferation, leads to dedifferentiation of primary beta cells and reduces glucose stimulated insulin secretion 11 . Furthermore, overexpression of the oncogene c-Myc in adult mouse beta cells increases proliferation and beta cells acquire an immature phenotype 12 . Conversely, removal of immortalizing transgenes in EndoC-βH1 cell line, a proliferative immortalized beta cell line generated from human fetal pancreas, decreases cell proliferation and enhances a number of beta cell specific features such as increased insulin gene expression and content 13 .…”