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Nicotinamide promotes pancreatic differentiation through the dual inhibition of CK1 and ROCK kinases in human embryonic stem cells
Zhang, Yumeng1,2; Xu, Jiaqi1,2; Ren, Zhili1,2; Meng, Ya1,2,3; Liu, Weiwei1,4; Lu, Ligong3; Zhou, Zhou5; Chen, Guokai1,2,6
2021-12-01
Source PublicationStem Cell Research and Therapy
ISSN1757-6512
Volume12Issue:1
Abstract

Background: Vitamin B3 (nicotinamide) plays important roles in metabolism as well as in SIRT and PARP pathways. It is also recently reported as a novel kinase inhibitor with multiple targets. Nicotinamide promotes pancreatic cell differentiation from human embryonic stem cells (hESCs). However, its molecular mechanism is still unclear. In order to understand the molecular mechanism involved in pancreatic cell fate determination, we analyzed the downstream pathways of nicotinamide in the derivation of NKX6.1 pancreatic progenitors from hESCs. Methods: We applied downstream modulators of nicotinamide during the induction from posterior foregut to pancreatic progenitors, including niacin, PARP inhibitor, SIRT inhibitor, CK1 inhibitor and ROCK inhibitor. The impact of those treatments was evaluated by quantitative real-time PCR, flow cytometry and immunostaining of pancreatic markers. Furthermore, CK1 isoforms were knocked down to validate CK1 function in the induction of pancreatic progenitors. Finally, RNA-seq was used to demonstrate pancreatic induction on the transcriptomic level. Results: First, we demonstrated that nicotinamide promoted pancreatic progenitor differentiation in chemically defined conditions, but it did not act through either niacin-associated metabolism or the inhibition of PARP and SIRT pathways. In contrast, nicotinamide modulated differentiation through CK1 and ROCK inhibition. We demonstrated that CK1 inhibitors promoted the generation of PDX1/NKX6.1 double-positive pancreatic progenitor cells. shRNA knockdown revealed that the inhibition of CK1α and CK1ε promoted pancreatic progenitor differentiation. We then showed that nicotinamide also improved pancreatic progenitor differentiation through ROCK inhibition. Finally, RNA-seq data showed that CK1 and ROCK inhibition led to pancreatic gene expression, similar to nicotinamide treatment. Conclusions: In this report, we revealed that nicotinamide promotes generation of pancreatic progenitors from hESCs through CK1 and ROCK inhibition. Furthermore, we discovered the novel role of CK1 in pancreatic cell fate determination.

KeywordCasein Kinase 1 (Ck1) Human Embryonic Stem Cells Kinase Inhibitor Nicotinamide Pancreatic Progenitors Rho-associated Protein Kinase (Rock)
DOI10.1186/s13287-021-02426-2
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaCell Biology ; Research & Experimental Medicine
WOS SubjectCell & Tissue Engineering ; Cell Biology ; Medicine, Research & Experimental
WOS IDWOS:000666977000001
Scopus ID2-s2.0-85108811455
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Cited Times [WOS]:5   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorChen, Guokai
Affiliation1.Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macao
2.Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macao
3.Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Jinan University, Zhuhai, China
4.Bioimaging and Stem Cell Core Facility, Faculty of Health Sciences, University of Macau, Macao
5.State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
6.MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao
First Author AffilicationCentre of Reproduction, Development and Aging;  Faculty of Health Sciences
Corresponding Author AffilicationCentre of Reproduction, Development and Aging;  Faculty of Health Sciences;  University of Macau
Recommended Citation
GB/T 7714
Zhang, Yumeng,Xu, Jiaqi,Ren, Zhili,et al. Nicotinamide promotes pancreatic differentiation through the dual inhibition of CK1 and ROCK kinases in human embryonic stem cells[J]. Stem Cell Research and Therapy,2021,12(1).
APA Zhang, Yumeng,Xu, Jiaqi,Ren, Zhili,Meng, Ya,Liu, Weiwei,Lu, Ligong,Zhou, Zhou,&Chen, Guokai.(2021).Nicotinamide promotes pancreatic differentiation through the dual inhibition of CK1 and ROCK kinases in human embryonic stem cells.Stem Cell Research and Therapy,12(1).
MLA Zhang, Yumeng,et al."Nicotinamide promotes pancreatic differentiation through the dual inhibition of CK1 and ROCK kinases in human embryonic stem cells".Stem Cell Research and Therapy 12.1(2021).
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