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

Zaniar Ghazizadeh, Kao Der-I, Sadaf Amin, Brandoch Cook, Sahana Rao, Ting Zhou, Tuo Zhang, Zhaoying Xiang, Reyn Kenyon, Omer Kaymakcalan, Chengyang Liu, Todd Evans and Shuibing Chen ()
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Zaniar Ghazizadeh: Weill Cornell Medical College
Kao Der-I: Weill Cornell Medical College
Sadaf Amin: Weill Cornell Medical College
Brandoch Cook: Weill Cornell Medical College
Sahana Rao: Weill Cornell Medical College
Ting Zhou: Weill Cornell Medical College
Tuo Zhang: Weill Cornell Medical College
Zhaoying Xiang: Weill Cornell Medical College
Reyn Kenyon: 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

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00129-y

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