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.
We previously reported that 3T3-L1 and rat primary adipocytes secreted microvesicles, known as adipocyte-derived microvesicles (ADMs). In the present study, we further characterized the 3T3-L1 ADMs and found that they exhibited angiogenic activity in vivo. Antibody arrays and gelatin zymography analyses revealed that several angiogenic and antiangiogenic proteins, including leptin, TNFalpha, acidic fibroblast growth factor (FGFa), interferon-gamma, and matrix metalloprotease (MMP)-2 and MMP-9, were present in the ADMs. Gene expression of most of these angiogenic factors was induced in the adipose tissue of diet-induced obese mice. Furthermore, leptin, TNFalpha, and MMP-2 were up-regulated at the protein level in the adipocyte fractions prepared from epididymal adipose tissues of high-fat-diet-induced obese mice. ADMs induced cell migration and tube formation of human umbilical vein endothelial cells, which were partially suppressed by neutralizing antibodies to leptin, TNFalpha, or FGFa but not to interferon-gamma. Supporting these data, a mixture of leptin, TNFalpha, and FGFa induced tube formation. ADMs also promoted cell invasion of human umbilical vein endothelial cells through Matrigel, which was suppressed by the addition of the MMP inhibitor 1,10'-phenanthroline and a neutralizing antibody to MMP-2 but not to MMP-9. These results suggest that ADMs are associated with multiple angiogenic factors and play a role in angiogenesis in adipose tissue.
Mice were injected with human recombinant tPA (kindly provided by Eisai, Tokyo, Japan) intraperitoneally at a concentration of 1.25 3 106 IU = 1 mg/kg body weight daily or PBS for a total of 3 days. (Recommended tPA dosage in humans for clinical use is 10 mg/kg.)The corrected passage is printed below: Mice were injected with human recombinant tPA (kindly provided by Eisai, Tokyo, Japan) intraperitoneally at a concentration of 1.25 3 106 IU = 10 mg/kg body weight daily or PBS for a total of 3 days. (Recommended tPA dosage in humans for clinical use is 10 mg/kg.
Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases IntroductionThe fibrinolytic system includes a broad spectrum of proteolytic enzymes with physiologic and pathophysiologic functions in several processes such as hemostatic balance, tissue remodeling, tumor invasion, reproduction, and angiogenesis.The serine protease plasmin is responsible for the degradation of fibrin into soluble degradation products (fibrinolysis). Plasmin is generated through cleavage of the proenzyme plasminogen (Plg) by the urokinase plasminogen activator (uPA) or tissue-type plasminogen activator (tPA). tPA consists of a kringle-and trypsin-like serine protease domain. 1 The activity of uPA and tPA is regulated by specific plasminogen activator inhibitors. In the absence of fibrin, tPA displays low activity toward Plg. 2 In the presence of fibrin this activity is 2 orders of magnitude higher. The catalytic efficiency of tPA for activation of cell-bound Plg is approximately 10-fold higher than that in solution. Most cells bind Plg through its lysine binding sites with a high capacity but a relatively low affinity. 3 Plg receptors such as the integrin ␣M2 play an important role in macrophage motility. 4 CD11b/CD18 cells adhere to fibrin, but tPA by its ability to bind to CD11b, has been shown to induce local fibrinolysis and to render adherent cells into migrating cells. 5 tPA has been shown to have numerous biologic functions. For example, within the central nervous system (reviewed by Melchor and Strickland 6 ) tPA is expressed by neurons and microglial cells (resident macrophages of the brain and spinal cord), where it can generate plasmin to degrade a variety of nonfibrin substrates (eg, -amyloid), can act as a direct protease without Plg involvement (eg, for the activation of latent platelet-derived growth factor-CC), or can function as a nonproteolytic modulator (eg, of the N-methyl-D-aspartate receptors).Besides their fibrinolytic activities, plasmin and Plg activators are also implicated in tissue proliferation and cellular adhesion, because they can proteolytically degrade the extracellular matrix (ECM) and regulate the activation of both growth factors and matrix metalloproteinases (MMPs; for review, see Zorio et al 7 ). PAs and plasmin generation in specific microenvironments in the bone marrow (BM) may be one of the factors orchestrating hematopoiesis. 8,9 Plg activation promotes the release of Kit ligand from BM stromal cells. 9,10 Plasmin can cleave thrombopoietin, the master cytokine of megakaryopoiesis and platelet production, thereby decreasing its biol...
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