Involvement of Rictor/mTORC2 in cardiomyocyte differentiation of mouse embryonic stem cellsin vitro

Rictor is a key regulatory/structural subunit of the mammalian target of rapamycin complex 2 (mTORC2) and is required for phosphorylation of Akt at serine 473. It plays an important role in cell survival, actin cytoskeleton organization and other processes in embryogenesis. However, the role of Rict...

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Bibliographic Details
Published in:International journal of biological sciences 2017-01, Vol.13 (1), p.110
Main Authors: Zheng, Bei, Wang, Jiadan, Tang, Leilei, Tan, Chao, Zhao, Zhe, Xiao, Yi, Ge, Renshan, Zhu, Danyan
Format: Article
Language:English
Subjects:
Actin
AKT protein
Biomarkers
Cadherins
Cardiomyocytes
Cell survival
Connexin 43
Cytoskeleton
Differentiation
Electrophysiology
Embryogenesis
Embryonic growth stage
Heart
Heart diseases
Kinases
Mesoderm
Myocytes
N-Cadherin
Nkx2.5 protein
Phosphorylation
Pluripotency
Progenitor cells
Proteins
Rapamycin
Serine
Stem cell transplantation
Stem cells
TOR protein
Ventricle
α-Actinin
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Summary:Rictor is a key regulatory/structural subunit of the mammalian target of rapamycin complex 2 (mTORC2) and is required for phosphorylation of Akt at serine 473. It plays an important role in cell survival, actin cytoskeleton organization and other processes in embryogenesis. However, the role of Rictor/mTORC2 in the embryonic cardiac differentiation has been uncovered. In the present study, we examined a possible link between Rictor expression and cardiomyocyte differentiation of the mouse embryonic stem (mES) cells. Knockdown of Rictor by shRNA significantly reduced the phosphorylation of Akt at serine 473 followed by a decrease in cardiomyocyte differentiation detected by beating embryoid bodies. The protein levels of brachyury (mesoderm protein), Nkx2.5 (cardiac progenitor cell protein) and α-Actinin (cardiomyocyte biomarker) decreased in Rictor knockdown group during cardiogenesis. Furthermore, knockdown of Rictor specifically inhibited the ventricular-like cells differentiation of mES cells with reduced level of ventricular-specific protein, MLC-2v. Meanwhile, patch-clamp analysis revealed that shRNA-Rictor significantly increased the number of cardiomyocytes with abnormal electrophysiology. In addition, the expressions and distribution patterns of cell-cell junction proteins (Cx43/Desmoplakin/N-cadherin) were also affected in shRNA-Rictor cardiomyocytes. Taken together, the results demonstrated that Rictor/mTORC2 might play an important role in the cardiomyocyte differentiation of mES cells. Knockdown of Rictor resulted in inhibiting ventricular-like myocytes differentiation and induced arrhythmias symptom, which was accompanied by interfering the expression and distribution patterns of cell-cell junction proteins. Rictor/mTORC2 might become a new target for regulating cardiomyocyte differentiation and a useful reference for application of the induced pluripotent stem cells.
ISSN:1449-2288
DOI:10.7150/ijbs.16312