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Sci Rep. 2016 Nov 22;6:37388. doi: 10.1038/srep37388.

Connexin 32-mediated cell-cell communication is essential for hepatic differentiation from human embryonic stem cells.

Qin J1,2,3, Chang M2, Wang S1,2,3, Liu Z4, Zhu W4, Wang Y2, Yan F2, Li J5, Zhang B1,3, Dou G5, Liu J4, Pei X1,3, Wang Y2.

Author information

1
Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing 100850, China.
2
Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing 100850, China.
3
South China Research Center for Stem Cell and Regenerative Medicine, South China Institute of Biomedicine, Guangzhou 510005, China.
4
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
5
Laboratory of Hematological Pharmacology, Beijing Institute of Transfusion Medicine, Beijing 100850, China.

Abstract

Gap junction-mediated cell-cell interactions are highly conserved and play essential roles in cell survival, proliferation, differentiation and patterning. We report that Connexin 32 (Cx32)-mediated gap junctional intercellular communication (GJIC) is necessary for human embryonic stem cell-derived hepatocytes (hESC-Heps) during step-wise hepatic lineage restriction and maturation. Vitamin K2, previously shown to promote Cx32 expression in mature hepatocytes, up-regulated Cx32 expression and GJIC activation during hepatic differentiation and maturation, resulting in significant increases of hepatic markers expression and hepatocyte functions. In contrast, negative Cx32 regulator 2-aminoethoxydiphenyl borate blocked hESC-to-hepatocyte maturation and muted hepatocyte functions through disruption of GJIC activities. Dynamic gap junction organization and internalization are phosphorylation-dependent and the p38 mitogen-activated protein kinases pathway (MAPK) can negatively regulate Cxs through phosphorylation-dependent degradation of Cxs. We found that p38 MAPK inhibitor SB203580 improved maturation of hESC-Heps correlating with up-regulation of Cx32; by contrast, the p38 MAPK activator, anisomycin, blocked hESC-Heps maturation correlating with down-regulation of Cx32. These results suggested that Cx32 is essential for cell-cell interactions that facilitate driving hESCs through hepatic-lineage maturation. Regulators of both Cx32 and other members of its pathways maybe used as a promising approach on regulating hepatic lineage restriction of pluripotent stem cells and optimizing their functional maturation.

PMID:
27874032
PMCID:
PMC5118817
DOI:
10.1038/srep37388
[Indexed for MEDLINE]
Free PMC Article

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