Endocrine islet β-cell subtypes with differential function are derived from biochemically distinct embryonic endocrine islet progenitors that are regulated by maternal nutrients

TL;DR

This study shows that different types of beta cells in the pancreas develop from distinct embryonic progenitors, and maternal nutrition affects their function, which could help in preventing diabetes.

Contribution

The study identifies biochemically distinct embryonic progenitors that give rise to functionally different beta-cell subtypes and links maternal nutrition to DNA methylation changes affecting these subtypes.

Findings

Embryonic islet progenitors with distinct gene expression and DNA methylation produce functionally different beta-cell subtypes in adult mice.

Maternal overnutrition reduces the proportion of high-function beta-cell progenitors by deregulating DNA methyl transferase 3a.

The gene signature defining mouse beta-cell subtypes can also classify human beta cells, with reduced high-function subtypes in diabetic donors.

Abstract

Endocrine islet b cells comprise heterogenous cell subsets. Yet when/how these subsets are produced and how stable they are remain unknown. Addressing these questions is important for preventing/curing diabetes, because lower numbers of b cells with better secretory function is a high risk of this disease. Using combinatorial cell lineage tracing, scRNA-seq, and DNA methylation analysis, we show here that embryonic islet progenitors with distinct gene expression and DNA methylation produce b-cell subtypes of different function and viability in adult mice. The subtype with better function is enriched for genes involved in vesicular production/trafficking, stress response, and Ca2+-secretion coupling, which further correspond to differential DNA methylation in putative enhancers of these genes. Maternal overnutrition, a major diabetes risk factor, reduces the proportion of endocrine progenitors of the b-cell subtype with better-function via deregulating DNA methyl transferase 3a. Intriguingly, the gene signature that defines mouse b-cell subtypes can reliably divide human cells into two sub-populations while the proportion of b cells with better-function is reduced in diabetic donors. The implication of these results is that modulating DNA methylation in islet progenitors using maternal food supplements can be explored to improve b-cell function in the prevention and therapy of diabetes.

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