MiR-375 inhibits the hepatocyte growth factor-elicited migration of mesenchymal stem cells by downregulating Akt signaling
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The migration of mesenchymal stem cells (MSCs) is critical for their use in cell-based therapies. Accumulating evidence suggests that microRNAs are important regulators of MSC migration. Here, we report that the expression of miR-375 was downregulated in MSCs treated with hepatocyte growth factor (HGF), which strongly stimulates the migration of these cells. Overexpression of miR-375 decreased the transfilter migration and the migration velocity of MSCs triggered by HGF. In our efforts to determine the mechanism by which miR-375 affects MSC migration, we found that miR-375 significantly inhibited the activation of Akt by downregulating its phosphorylation at T308 and S473, but had no effect on the activity of mitogen-activated protein kinases. Further, we showed that 3’phosphoinositide-dependent protein kinase-1 (PDK1), an upstream kinase necessary for full activation of Akt, was negatively regulated by miR-375 at the protein level. Moreover, miR-375 suppressed the phosphorylation of focal adhesion kinase (FAK) and paxillin, two important regulators of focal adhesion (FA) assembly and turnover, and decreased the number of FAs at cell periphery. Taken together, our results demonstrate that miR-375 inhibits HGF-elicited migration of MSCs through downregulating the expression of PDK1 and suppressing the activation of Akt, as well as influencing the tyrosine phosphorylation of FAK and paxillin and FA periphery distribution.
KeywordsMesenchymal stem cells (MSCs) miR-375 Hepatocyte growth factor (HGF) Akt signaling PDK1 Focal adhesions (FAs) Cell migration
This work was supported by the National Natural Science Foundation of China (Grant no. 31371407, 30870642) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
LH and HZ designed the study, conducted all searches, appraised all potential studies and wrote and revised the draft manuscript and subsequent manuscripts. XW conceived and designed the study, assisted with searches, appraised relevant studies and assisted with drafting and revising the manuscript. NK assisted with searches and appraised relevant studies. JX, ND and XX assisted with drafting and revising the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
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