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

EL-KHAIRI, R.; OLSZANOWSKI, E.; MURARO, D.; MADRIGAL, P.; TILGNER, K.; CHHATRIWALA, M.; VYAS, S.; CHIA, C.Y.; VALLIER, L.; RODRÍGUEZ-SEGUÍ, S.A.

Stem Cell Reports

Cell Press

Lugar: Massachusetts; Año: 2021

2213-6711

Heterozygousmutations in HNF1Bin humans result in a multi-system disorder, including pancreatichypoplasia and diabetes mellitus. Here we used a well-controlledhuman induced pluripotent stem cell pancreatic differentiation modelto elucidate the molecular mechanisms underlying HNF1B-associateddiabetes. Our results showthat lackof HNF1B blocks specification of pancreatic fate from the foregutprogenitor (FP) stage, but HNF1B haploinsufficiency allowsdifferentiation of multipotent pancreatic progenitor cells (MPCs) andinsulin secreting β-like cells. Weshow that HNF1B haploinsufficiency impairscell proliferation in FPs and MPCs. This could be attributed toimpaired induction of key pancreatic developmental genes, includingSOX11,ROBO2,and additional TEAD1 target genes whose function is associated withMPC self-renewal. In this work we uncover an exhaustivelist of potential HNF1Bgene targets during human pancreas organogenesis whose downregulationmight underlie HNF1B-associated diabetes onset in humans, thusproviding an important resource to understand the pathogenesis ofthis disease.p { margin-bottom: 0.1in; direction: ltr; line-height: 115%; text-align: left; orphans: 2; widows: 2 }p.western { font-family: "Times New Roman", serif }p.cjk { font-family: "Times New Roman"; so-language: en-GB }p.ctl { font-family: "Times New Roman" }a:link { color: #0000ff }