The Plasminogen Fibrinolytic Pathway Is Required for Hematopoietic Regeneration

Abstract

Hematopoietic stem cells within the bone marrow exist in a quiescent state. They can differentiate and proliferate in response to hematopoietic stress (e.g., myelosuppression), thereby ensuring a well-regulated supply of mature and immature hematopoietic cells within the circulation. However, little is known about how this stress response is coordinated. Here, we show that plasminogen (Plg), a classical fibrinolytic factor, is a key player in controlling this stress response. Deletion of Plg in mice prevented hematopoietic stem cells from entering the cell cycle and undergoing multilineage differentiation after myelosuppression, leading to the death of the mice. Activation of Plg by administration of tissue-type plasminogen activator promoted matrix metalloproteinase-mediated release of Kit ligand from stromal cells, thereby promoting hematopoietic progenitor cell proliferation and differentiation. Thus, activation of the fibrinolytic cascade is a critical step in regulating the hematopoietic stress response.

New functions of the fibrinolytic system in bone marrow cell-derived angiogenesis

“…Both VEGF-A and KitL can expand the CD11b? myeloid cell pool within the bone marrow [32] Plasmin regulates angiogenesis via MMP activation 135…”

“…We showed that MMP-9 participates in progenitor cell mobilization and the hematopoietic regeneration process within the BM by mediating the shedding of soluble forms of membrane-bound cytokines such as kit ligand (KitL, also known as stem cell factor or SCF) and induced SDF-1 [30]. These data regarding MMP-9 function were extended by a study that demonstrated that MMP-mediated release of KitL was blocked in Plg-deficient mice [32,33]. Indeed, proteinasemediated inactivation of cytokine signals such as c-kit/KitL and SDF-1/C-X-C chemokine receptor type 4 (CXCR4), which anchor hematopoietic progenitor stem cells (HPSCs) in the BM microenvironment, is central to the regulation of HPSC mobilization: the inactivation of these cytokine signals allows HPSCs to proliferate, migrate to the sinusoidal capillaries, and eventually enter the peripheral blood.…”

“…Since the fibrinolytic system can regulate MMP activity, and MMP activity has been shown to be an essential part of BM cell recruitment, we hypothesized that BM cell recruitment would be modulated by activation of the fibrinolytic system. We showed that activation of the extracellular proteases MMP-9 and plasmin by a serpin-resistant form of tPA expanded the myeloid cell pool [32] and mobilized CD45?CD11b? pro-angiogenic, myeloid cells from the BM, a process that is dependent on VEGF-A and KitL signaling (Fig.…”

“…Plasmin has also been implicated as a mediator of HPSC mobilization from the BM to the circulation [32,36].…”

Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking

“…[12][13][14] The role of plm in guiding the cytokine storm is not well understood. Because plm can activate other proteases like metalloproteinases (MMPs) [15][16][17] and some MMP inhibitors can block processing of TNF-a and Fasligand (FasL), [18][19][20][21][22] we hypothesized that plm activation may control the cytokine storm and regulate the inflammatory response in murine models of aGVHD.…”