Abstract
SummaryHeterozygous mutations in HNF1B in humans result in a multisystem disorder, including pancreatic hypoplasia and diabetes mellitus. Here we used a well-controlled human induced pluripotent stem cell pancreatic differentiation model to elucidate the molecular mechanisms underlying HNF1B-associated diabetes. Our results show that lack of HNF1B blocks specification of pancreatic fate from the foregut progenitor (FP) stage, but HNF1B haploinsufficiency allows differentiation of multipotent pancreatic progenitor cells (MPCs) and insulin-secreting β-like cells. We show that HNF1B haploinsufficiency impairs cell proliferation in FPs and MPCs. This could be attributed to impaired induction of key pancreatic developmental genes, including SOX11, ROBO2, and additional TEAD1 target genes whose function is associated with MPC self-renewal. In this work we uncover 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.
Highlights
Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, and it is characterized by autosomal dominant inheritance, onset typically before 25 years of age, and hyperglycemia due to b cell failure
Consistent with findings using our previous protocol, hepatic nuclear factor 1b (HNF1B) expression was upregulated at the foregut progenitor (FP) stage (Figure 1B)
At the pancreatic multipotent progenitor cell (MPC) stage, >90% PDX1+ cells were detected, and HNF1B was still co-expressed with PDX1 in almost all cells, and around 50% of cells co-expressed NKX6.1 ($60% in FSPS13.B and $40% in Eipl_1) (Figures 1C, 1D, S1A–S1C and data not shown)
Summary
Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, and it is characterized by autosomal dominant inheritance, onset typically before 25 years of age, and hyperglycemia due to b cell failure. The most common clinical features include renal disease, pancreatic hypoplasia, and diabetes mellitus, which typically develops during adolescence or early adulthood. More than 50 splice-site, nonsense, missense, and frameshift mutations in the HNF1B gene have been reported to date, as well as partial or whole gene deletions (Clissold et al, 2014). Patients with whole-gene deletions do not exhibit a phenotype different from those with coding or splice-site mutations, suggesting that dysfunction is due to a gene-dosage effect, i.e., haploinsufficiency (Bellanne-Chantelot et al, 2005; Edghill et al, 2006b)
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