Bone Marrow Mesenchymal Stromal Cells Stimulate Skeletal Myoblast Proliferation through the Paracrine Release of VEGF
Open Access
- 16 July 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (7), e37512
- https://doi.org/10.1371/journal.pone.0037512
Abstract
Mesenchymal stromal cells (MSCs) are the leading cell candidates in the field of regenerative medicine. These cells have also been successfully used to improve skeletal muscle repair/regeneration; however, the mechanisms responsible for their beneficial effects remain to be clarified. On this basis, in the present study, we evaluated in a co-culture system, the ability of bone-marrow MSCs to influence C2C12 myoblast behavior and analyzed the cross-talk between the two cell types at the cellular and molecular level. We found that myoblast proliferation was greatly enhanced in the co-culture as judged by time lapse videomicroscopy, cyclin A expression and EdU incorporation. Moreover, myoblasts immunomagnetically separated from MSCs after co-culture expressed higher mRNA and protein levels of Notch-1, a key determinant of myoblast activation and proliferation, as compared with the single culture. Notch-1 intracellular domain and nuclear localization of Hes-1, a Notch-1 target gene, were also increased in the co-culture. Interestingly, the myoblastic response was mainly dependent on the paracrine release of vascular endothelial growth factor (VEGF) by MSCs. Indeed, the addition of MSC-derived conditioned medium (CM) to C2C12 cells yielded similar results as those observed in the co-culture and increased the phosphorylation and expression levels of VEGFR. The treatment with the selective pharmacological VEGFR inhibitor, KRN633, resulted in a marked attenuation of the receptor activation and concomitantly inhibited the effects of MSC-CM on C2C12 cell growth and Notch-1 signaling. In conclusion, this study provides novel evidence for a role of MSCs in stimulating myoblast cell proliferation and suggests that the functional interaction between the two cell types may be exploited for the development of new and more efficient cell-based skeletal muscle repair strategies.Keywords
This publication has 41 references indexed in Scilit:
- Therapeutic factors secreted by mesenchymal stromal cells and tissue repairJournal of Cellular Biochemistry, 2011
- Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recoveryExperimental Cell Research, 2009
- Distinct Origins and Genetic Programs of Head Muscle Satellite CellsDevelopmental Cell, 2009
- Treatment of Experimental Injury of Anal Sphincters with Primary Surgical Repair and Injection of Bone Marrow-Derived Mesenchymal Stem CellsDiseases of the Colon & Rectum, 2008
- Muscle Satellite Cells and Endothelial Cells: Close Neighbors and Privileged PartnersMolecular Biology of the Cell, 2007
- Cultured slow vs. fast skeletal muscle cells differ in physiology and responsiveness to stimulationAmerican Journal of Physiology-Cell Physiology, 2006
- Direct Isolation of Satellite Cells for Skeletal Muscle RegenerationScience, 2005
- Bone Marrow Stromal Cells Generate Muscle Cells and Repair Muscle DegenerationScience, 2005
- Vascular Endothelial Growth Factor Modulates Skeletal Myoblast FunctionThe American Journal of Pathology, 2003
- Expression of Cd34 and Myf5 Defines the Majority of Quiescent Adult Skeletal Muscle Satellite CellsThe Journal of cell biology, 2000