The view depicting bone marrow (BM)-derived mesenchymal stem cells (MSC) as a uniform population differentiating into new-tissue builder cells is evolving toward the concept of a heterogeneous population of stem/progenitor cells secreting bioactive molecules, and contributing to establish an on-site regenerative microenvironment. We report that in an ectopic bone formation model the intrinsic MSC capability to activate endogenous regenerative mechanisms is critically dependent on the commitment level of implanted MSC. We demonstrate that the presence of bFGF in the culture medium during mouse MSC expansion in vitro is the key factor for the selection of subpopulations inducing host regenerative responses. We developed a novel strategy combining SILAC-LC-MS/MS quantitative proteomics of conditioned culture media and gene expression profiling to disentangle the major role of MSC in modulating the microenvironment toward the damage resolution. The correspondence between results provided by the applied techniques proved that the most statistically significant biological processes favored by the bFGF treatment were carried out by secreted factors. In particular, the immune response, the inflammatory response, the response to wounding and chemotaxis were all upregulated in bFGF-selected MSC. We propose these processes as majorly involved in activating the endogenous responses triggered by trophic effects of implanted bFGF-selected MSC.
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