Fibrinolytic crosstalk with endothelial cells expands murine mesenchymal stromal cells

Tissue plasminogen activator (tPA), aside from its vascular fibrinolytic action, exerts various effects within the body, ranging from synaptic plasticity to control of cell fate. Here, we observed that by activating plasminogen and matrix metalloproteinase-9, tPA expands murine bone marrow–derived CD45−TER119−Sca-1+PDGFRα+ mesenchymal stromal cells (PαS-MSCs) in vivo through a crosstalk between PαS-MSCs and endothelial cells. Mechanistically, tPA induces the release of Kit ligand from PαS-MSCs, which activates c-Kit+ endothelial cells to secrete MSC growth factors: platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor 2 (FGF2). In synergy, FGF2 and PDGF-BB upregulate PDGFRα expression in PαS-MSCs, which ultimately leads to PαS-MSC expansion. These data show a novel mechanism by which the fibrinolytic system expands PαS-MSCs through a cytokine crosstalk between niche cells. •tPA expands mesenchymal stromal cells (MSCs) in the bone marrow by a cytokine (KitL and PDGF-BB) crosstalk with endothelial cells.•Pharmacologic inhibition of receptor tyrosine kinases (c-Kit and PDGFRα) impairs tPA-mediated MSC proliferation.