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Modelling HNF1B-associated monogenic diabetes using human iPSCs reveals an early stage impairment of the pancreatic developmental program

ABSTRACT: Heterozygous mutations in HNF1B in humans result in a multi-system disorder, including pancreatic hypoplasia and diabetes mellitus. The underlying mechanisms that contribute to disease pathogenesis remain largely unknown, partially accounted by the fact that mouse models with heterozygous deletions in Hnf1b do not develop diabetes, in contrast to the phenotypes observed in MODY patients. Here we used a well-controlled human induced pluripotent stem cell pancreatic differentiation model to elucidate the molecular mechanisms underlying HNF1B-associated diabetes and pancreatic hypoplasia. Our results show that lack of HNF1B blocks specification of pancreatic fate from the foregut progenitor stage, but HNF1B haploinsufficiency allows differentiation of multipotent pancreatic progenitor cells and insulin secreting β-like cells. We further report that HNF1B happloinsuffiency impairs cell proliferation in foregut and multipotent pancreatic progenitors (MPCs). Our analyses suggest that this could be attributed to impaired induction of key pancreatic developmental genes, including FOXA1, SOX11, ROBO2, and additional TEAD1 target genes whose function could be associated with MPCs self-renewal. Taken together, these analyses have uncovered an exhaustive list of potential HNF1B gene targets during human pancreas organogenesis whose downregulation might underlie HNF1B-associated diabetes onset in humans, thus providing an important resource to understand the pathogenesis of this disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168071 | GEO | 2021/07/26

REPOSITORIES: GEO

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