Elucidation of HHEX in pancreatic endoderm differentiation using a human iPSC differentiation model

For pluripotent stem cell (PSC)-based regenerative therapy against diabetes, the differentiation efficiency to pancreatic lineage cells needs to be improved based on the mechanistic understanding of pancreatic differentiation. Here, we aimed to elucidate the molecular mechanisms underlying pancreati...

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Bibliographic Details
Published in:Scientific reports 2023-05, Vol.13 (1), p.8659-8659, Article 8659
Main Authors: Ito, Ryo, Kimura, Azuma, Hirose, Yurie, Hatano, Yu, Mima, Atsushi, Mae, Shin-Ichi, Keidai, Yamato, Nakamura, Toshihiro, Fujikura, Junji, Nishi, Yohei, Ohta, Akira, Toyoda, Taro, Inagaki, Nobuya, Osafune, Kenji
Format: Article
Language:English
Subjects:
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Cell differentiation
Cell Differentiation - genetics
Diabetes
Diabetes mellitus
Efficiency
Endoderm
Genes
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humanities and Social Sciences
Humans
Hyperglycemia
Induced Pluripotent Stem Cells
Molecular modelling
multidisciplinary
Nkx6.1 protein
Pancreas
Pancreas - metabolism
Pluripotency
Protein expression
Science
Science (multidisciplinary)
siRNA
Stem cells
Trans-Activators - genetics
Trans-Activators - metabolism
Transcription factors
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary:For pluripotent stem cell (PSC)-based regenerative therapy against diabetes, the differentiation efficiency to pancreatic lineage cells needs to be improved based on the mechanistic understanding of pancreatic differentiation. Here, we aimed to elucidate the molecular mechanisms underlying pancreatic endoderm differentiation by searching for factors that regulate a crucial pancreatic endoderm marker gene, NKX6.1. Unbiasedly screening an siRNA knockdown library, we identified a candidate transcription factor, HHEX. HHEX knockdown suppressed the expression of another pancreatic endoderm marker gene, PTF1A , as well as NKX6.1 , independently of PDX1 , a known regulator of NKX6.1 expression. In contrast, the overexpression of HHEX upregulated the expressions of NKX6.1 and PTF1A . RNA-seq analysis showed decreased expressions of several genes related to pancreatic development, such as NKX6.1 , PTF1A , ONECUT1 and ONECUT3 , in HHEX knockdown pancreatic endoderm. These results suggest that HHEX plays a key role in pancreatic endoderm differentiation.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-35875-1