Thrombospondin-1 promotes mesenchymal stromal cell functions via TGFβ and in cooperation with PDGF

Mesenchymal stromal cells (MSC) are characterized by unique tropism for wounded tissues, high differentiating capacity, ability to induce tissue repair, and anti-inflammatory and immunoregulatory activities. This has generated interest in their therapeutic use in severe human conditions as well as in regenerative medicine and tissue engineering. Identification of factors involved in the regulation of MSC proliferation, migration and differentiation could provide insights into the pathophysiological regulation of MSC and be exploited to optimize clinical grade expansion protocols for therapeutic use. Here we identify thrombospondin-1 (TSP-1) as a major regulator of MSC. TSP-1 induced MSC proliferation. This effect was mediated by TSP-1-induced activation of endogenous TGFβ, as shown by the inhibitory effects of anti-TGFβ antibodies and by the lack of activity of TSP-2 - that does not activate TGFβ. Moreover, TSP-1 strongly potentiated the proliferative and migratory activity of PDGF on MSC. TSP-1 directly bound to PDGF, through a site located within the TSP-1 type III repeats, and protected the growth factor from degradation by MSC-derived proteases, hence increasing its stability and bioavailability. The studies presented here identify a more comprehensive picture of the pleiotropic effect of TSP-1 on MSC behavior, setting the basis for further studies aimed at investigating the possible use of PDGF and TSP-1 in the in vitro expansion of MSC for therapeutic applications.