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

Autor:	El-Khairi R; Wellcome Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Olszanowski E; Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina., Muraro D; Wellcome Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Madrigal P; Wellcome Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Tilgner K; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Chhatriwala M; Wellcome Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Vyas S; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Chia CY; Wellcome Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Hinxton, Cambridge, UK., Vallier L; Wellcome Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Hinxton, Cambridge, UK; Department of Surgery, University of Cambridge, Cambridge, UK. Electronic address: lv225@cam.ac.uk., Rodríguez-Seguí SA; Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina; Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: srodriguez@fbmc.fcen.uba.ar.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2021 Sep 14; Vol. 16 (9), pp. 2289-2304. Date of Electronic Publication: 2021 Aug 26.
DOI:	10.1016/j.stemcr.2021.07.018
Abstrakt:	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. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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