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Modeling HNF1B-associated monogenic diabetes using human iPSCs reveals an early stage impairment of the pancreatic developmental program
Stem Cell Reports ( IF 5.9 ) Pub Date : 2021-08-26 , DOI: 10.1016/j.stemcr.2021.07.018
Ranna El-Khairi 1 , Evelyn Olszanowski 2 , Daniele Muraro 3 , Pedro Madrigal 3 , Katarzyna Tilgner 4 , Mariya Chhatriwala 3 , Sapna Vyas 4 , Crystal Y Chia 3 , Ludovic Vallier 5 , Santiago A Rodríguez-Seguí 6
Affiliation  

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.



中文翻译:

使用人类 iPSC 对 HNF1B 相关的单基因糖尿病进行建模揭示了胰腺发育程序的早期损害

人类HNF1B的杂合突变导致多系统疾病,包括胰腺发育不全和糖尿病。在这里,我们使用控制良好的人类诱导多能干细胞胰腺分化模型来阐明 HNF1B 相关糖尿病的分子机制。我们的研究结果表明,HNF1B 的缺乏阻止了前肠祖细胞 (FP) 阶段胰腺命运的规范,但 HNF1B 单倍体不足允许多能胰腺祖细胞 (MPC) 和分泌胰岛素的 β 样细胞分化。我们表明 HNF1B 单倍体不足会损害 FP 和 MPC 中的细胞增殖。这可能归因于关键胰腺发育基因的诱导受损,包括SOX11ROBO2,以及其他与 MPC 自我更新相关的 TEAD1 靶基因。在这项工作中,我们揭示了人类胰腺器官发生过程中潜在HNF1B基因靶点的详尽列表,其下调可能是人类 HNF1B 相关糖尿病发病的基础,从而为了解这种疾病的发病机制提供了重要资源。

更新日期:2021-09-14
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