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ROCKII inhibition promotes the maturation of human pancreatic beta-like cells

Author

Listed:
  • Zaniar Ghazizadeh

    (Weill Cornell Medical College
    Weill Cornell Medical College)

  • Der-I Kao

    (Weill Cornell Medical College
    Weill Cornell Medical College)

  • Sadaf Amin

    (Weill Cornell Medical College
    Weill Cornell Medical College)

  • Brandoch Cook

    (Weill Cornell Medical College)

  • Sahana Rao

    (Weill Cornell Medical College
    Weill Cornell Medical College)

  • Ting Zhou

    (Weill Cornell Medical College
    Weill Cornell Medical College)

  • Tuo Zhang

    (Weill Cornell Medical College)

  • Zhaoying Xiang

    (Weill Cornell Medical College)

  • Reyn Kenyon

    (Weill Cornell Medical College
    Weill Cornell Medical College)

  • Omer Kaymakcalan

    (Weill Cornell Medical College)

  • Chengyang Liu

    (University of Pennsylvania School of Medicine)

  • Todd Evans

    (Weill Cornell Medical College)

  • Shuibing Chen

    (Weill Cornell Medical College
    Weill Cornell Medical College)

Abstract

Diabetes is linked to loss of pancreatic beta-cells. Pluripotent stem cells offer a valuable source of human beta-cells for basic studies of their biology and translational applications. However, the signalling pathways that regulate beta-cell development and functional maturation are not fully understood. Here we report a high content chemical screen, revealing that H1152, a ROCK inhibitor, promotes the robust generation of insulin-expressing cells from multiple hPSC lines. The insulin expressing cells obtained after H1152 treatment show increased expression of mature beta cell markers and improved glucose stimulated insulin secretion. Moreover, the H1152-treated beta-like cells show enhanced glucose stimulated insulin secretion and increased capacity to maintain glucose homeostasis after transplantation. Conditional gene knockdown reveals that inhibition of ROCKII promotes the generation and maturation of glucose-responding cells. This study provides a strategy to promote human beta-cell maturation and identifies an unexpected role for the ROCKII pathway in the development and maturation of beta-like cells.

Suggested Citation

  • Zaniar Ghazizadeh & Der-I Kao & Sadaf Amin & Brandoch Cook & Sahana Rao & Ting Zhou & Tuo Zhang & Zhaoying Xiang & Reyn Kenyon & Omer Kaymakcalan & Chengyang Liu & Todd Evans & Shuibing Chen, 2017. "ROCKII inhibition promotes the maturation of human pancreatic beta-like cells," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00129-y
    DOI: 10.1038/s41467-017-00129-y
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    Cited by:

    1. Qing Ma & Yini Xiao & Wenjun Xu & Menghan Wang & Sheng Li & Zhihao Yang & Minglu Xu & Tengjiao Zhang & Zhen-Ning Zhang & Rui Hu & Qiang Su & Fei Yuan & Tinghui Xiao & Xuan Wang & Qing He & Jiaxu Zhao , 2022. "ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Frankie Poon & Rangarajan Sambathkumar & Roman Korytnikov & Yasaman Aghazadeh & Amanda Oakie & Paraish S. Misra & Farida Sarangi & M. Cristina Nostro, 2024. "Tankyrase inhibition promotes endocrine commitment of hPSC-derived pancreatic progenitors," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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