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.
- Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y, Tajima N, Yamada H, Sawada H, Ishikawa H, Mimura T, Kitada M, Suzuki Y, Ide C (2004) Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113:1701–1710CrossRefPubMedPubMedCentralGoogle Scholar
- Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, Taccioli C, Pichiorri F, Alder H, Secchiero P, Gasparini P, Gonelli A, Costinean S, Acunzo M, Condorelli G, Croce CM (2009) miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16:498–509CrossRefPubMedPubMedCentralGoogle Scholar
- Marconi S, Castiglione G, Turano E, Bissolotti G, Angiari S, Farinazzo A, Constantin G, Bedogni G, Bedogni A, Bonetti B (2012) Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Eng Part A 18:1264–1272CrossRefPubMedGoogle Scholar
- Ryu CH, Park SA, Kim SM, Lim JY, Jeong CH, Jun JA, Oh JH, Park SH, Oh WI, Jeun SS (2010) Migration of human umbilical cord blood mesenchymal stem cells mediated by stromal cell-derived factor-1/CXCR4 axis via Akt, ERK, and p38 signal transduction pathways. Biochem Biophys Res Commun 398:105–110CrossRefPubMedGoogle Scholar
- Sordi V, Malosio ML, Marchesi F, Mercalli A, Melzi R, Giordano T, Belmonte N, Ferrari G, Leone BE, Bertuzzi F, Zerbini G, Allavena P, Bonifacio E, Piemonti L (2005) Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 106:419–427CrossRefPubMedGoogle Scholar
- Xia H, Nho RS, Kahm J, Kleidon J, Henke CA (2004) Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem 279:33024–33034CrossRefPubMedGoogle Scholar