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

Stem Cell Reports
R El-KhairiSantiago A Rodríguez-Seguí

Abstract

Heterozygous 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.

References

Nov 24, 1999·Mechanisms of Development·C CoffinierM Yaniv
Jan 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·C HaumaitreS Cereghini
Jun 3, 2005·Journal of Medical Genetics·E L EdghillA T Hattersley
Sep 10, 2013·Genes & Development·Elisa Rodríguez-SeguelFrancesca M Spagnoli
Sep 17, 2013·Cell Reports·Brandon L TaylorMaike Sander
Dec 24, 2014·Nature Reviews. Nephrology·Rhian L ClissoldCoralie Bingham
Apr 29, 2015·Nature Cell Biology·Inês CebolaJorge Ferrer
Dec 9, 2015·Mechanisms of Development·Stefanie J WillmannHeiko Lickert
Jan 28, 2016·Genome Biology·Ana ConesaAli Mortazavi
Feb 16, 2016·Stem Cell Reports·Adrian Kee Keong TeoRohit N Kulkarni
Sep 13, 2016·Diabetes, Obesity & Metabolism·R El-Khairi, L Vallier
Nov 28, 2017·Journal of Hepatology·Hwee Hui LauAdrian Kee Keong Teo
Feb 8, 2018·Genome Biology·F Alexander WolfFabian J Theis
Dec 7, 2018·Nature Communications·Sophie EscotFrancesca M Spagnoli
May 10, 2019·Nature·Adrian VeresDouglas A Melton
Jul 24, 2021·Frontiers in Endocrinology·Juan Ignacio BurgosSantiago A Rodríguez-Seguí

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cambridge Stem Cell Institute - Researcher Network

Cambridge Stem Cell Institute's mission is to transform human health through a deep understanding of stem cell biology. Follow this feed to stay up to date on research published in this group.