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Cited by 60Pancreatic function and diabetesPluripotent Stem Cells ResearchDiabetes and associated disorders

Human expandable pancreatic progenitor–derived β cells ameliorate diabetes

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Ma, Xiaojie, Lu, Yunkun, Zhou, Ziyu, Li, Qin, Chen, Xi, Wang, Weiyun, Jin, Yan, Hu, Zhensheng +8 more·2022·Science Advances
DOI 10.1126/sciadv.abk1826PMC PMC8865776
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Abstract

An unlimited source of human pancreatic β cells is in high demand. Even with recent advances in pancreatic differentiation from human pluripotent stem cells, major hurdles remain in large-scale and cost-effective production of functional β cells. Here, through chemical screening, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor I-BET151 can robustly promote the expansion of PDX1 + NKX6.1 + pancreatic progenitors (PPs). These expandable PPs (ePPs) maintain pancreatic progenitor cell status in the long term and can efficiently differentiate into functional pancreatic β (ePP-β) cells. Notably, transplantation of ePP-β cells rapidly ameliorated diabetes in mice, suggesting strong potential for cell replacement therapy. Mechanistically, I-BET151 activates Notch signaling and promotes the expression of key PP-associated genes, underscoring the importance of epigenetic and transcriptional modulations for lineage-specific progenitor self-renewal. In summary, our studies achieve the long-term goal of robust expansion of PPs and represent a substantial step toward unlimited supplies of functional β cells for biomedical research and regenerative medicine.

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  • Defined culture media containing either SB431542 or I-BET151 promoted the expansion of PDX1+/NKX6-1+ human pancreatic progenitors.

    “In particular, it was recently reported that defined culture media containing either the TGF-β pathway inhibitor SB431542183 or I-BET151,184 an inhibitor of the acetyl-lysine bromodomain-containing proteins, promoted the expansion of PDX1+/NKX6-1+ human pancreatic progenitors.”

    From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [184]

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Authors
Ma, X., Lu, Y., Zhou, Z., Li, Q., Chen, X., Wang, W., Jin, Y., Hu, Z., Chen, G., Deng, Q., Shang, W., Wang, H., Fu, H., He, X., Feng, X.-H., & Zhu, S.
Affiliations
  • Zhejiang University (CN)
  • The MOE Key Laboratory of Biosystems Homeostasis and Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • Hangzhou Women’s Hospital (CN)
  • Zhejiang Shuren University (CN)
  • Second Affiliated Hospital of Zhejiang University (CN)
Corresponding author
  • Lu, Yunkun
  • Zhou, Ziyu
  • Li, Qin
  • Zhu, Saiyong
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-02-25
Volume
8
Issue
8
Pages
eabk1826-eabk1826
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abk1826
PMC
PMC8865776
OpenAlex
W4213179684
Cited by
60
References
56
Citations by year
2026: 6 · 2025: 8 · 2024: 25 · 2023: 15 · 2022: 6
FWCI
12.89
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
pancreatic progenitor cells, beta-cell expansion, I-BET151, BET inhibitors, Notch signaling, PDX1, NKX6.1, epigenetic regulation, cell replacement therapy, diabetes mellitus, cell transplantation, regenerative medicine, self-renewal
MeSH terms
Animals, Cell Differentiation, Diabetes Mellitus, Humans, Trans-Activators, Homeodomain Proteins, Pluripotent Stem Cells, Insulin-Secreting Cells, Mice

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