Novel Functions for a Fibrinolytic Pathway in Controlling the Stem Cell Niche.

Hematopoietic stem cells (HSCs) reside within specific niches, where they are maintained by self-renewal and can be mobilized into circulation, but the underlying mechanisms are still unknown. The hematopoietic niche comprises of a local network of stromal cells (like fibroblasts, endothelial cells), accessory cells (T lymphocytes, monocytes), their products (extracellular matrix (ECM) and cytokines, capable of influencing self-renewal, proliferation and differentiation of HSCs. One such ECM molecule is fibrin, which can be found along surfaces in the bone marrow. Its precursor fibrinogen can maintain hematopoiesis in long-term bone marrow liquid cultures and increase the colony size of bone marrow cells cultured in semisolid medium containing serum. Plasmin, a serine protease, proteolytically degrades fibrin and fibrinogen. Plasminogen (Plg), its inactive proenzyme is present in the plasma, interstitial fluid or adherent to ECM proteins and can be activated by tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and other serine proteasesWe demonstrated previously that matrix metalloproteinase-9 (MMP-9) controls stem cell recruitment from the bone marrow niche. During fibrinolysis plasmin participates in the consecutive activation of MMPs. We initially wished to determine if this fibrinolytic cascade might be involved in regulating the stem cell niche. In this study we provide novel mechanistic data demonstrating that classical fibrinolytic factors-Plg/Plasmin are involved in recruitment of HSCs into the cell cycle following myelosuppression and their mobilization from the BM niche influencing cell differentiation, proliferation and migration by activating niche cells to secrete typical niche factors, including Kit-ligand and stromal cell-derived factor-1 (SDF-1, CXCL12). Deletion of Plg in mice prevented hematopoietic stem cells from entering the cell cycle and undergoing differentiation after myelosuppression, leading to the death of the mice. By Plg-dependent and Plg-independent pathways, tissue-type plasminogen activator activated matrix metalloproteinases and released Kit ligand and stromal cell-derived factor-1 from niche cells, thereby promoting stem cell recruitment and proliferation. We conclude that the fibrinolytic cascade plays a critical role in controlling the exit from the stem cell niche and that this represents a general stem cell regulatory axis.