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発表内容

Title:
Protease activation triggers the process of tissue regeneration

Koichi Hattori 1, 2
1Center for Genome and Regenerative Medicine, Juntendo University School of Medicine,
2Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science ,University of Tokyo

Abstract:
The concept of angiogenesis including vasculogenesis, a process by which new blood vessels form from preexisting vasculature, is one of the key components during tissue regeneration. This process includes the differentiation of hemangioblasts into endothelial cells with the help of secreted angiogenic factors released from bone marrow (BM)-derived cells such as macrophage, neutrophils, mast cells and other tissue progenitors. The fibrinolytic factor plasmin, which is one of the serine proteases, has been shown to promote endothelial cell migration either directly by degrading matrix proteins such as fibrin, or indirectly by converting matrix-bound angiogenic growth factors into its soluble form. Plasmin can also activate other pericellular proteases such as soluble and membrane type of matrix metalloproteinases (MMPs). MMPs catalyze the normal turnover of extracellular matrix (ECM) macromolecules such as interstitial and basement membrane collagens, proteoglycans and adhesion molecules, typical representatives of accessory ECM proteins. In addition to its necessity for matrix-remodeling, ECM degradation also leads to the release of matrix-bound signaling molecules. Furthermore, MMPs directly promote ectodomain shedding-processing of cytokine, chemokines, growth factors, cell surface receptors and the other proteases.
Recent studies indicate that plasmin can additionally alter cellular adhesion and migration. We showed that factors of the fibrinolytic pathway recruit BM-derived hematopoietic cells into ischemic and hypoxic tissues by altering the activation status of MMPs. These BM-derived cells can function as accessory cells that promote angiogenesis by releasing angiogenic and growth signals. We will introduce our recent data regarding the role of the fibrinolytic system in controlling myeloid cell-driven angiogenesis and other biological phenomena. We propose that the fibrinolytic system, and here above all the plasmin-plasminogen axis may be a potential target not only for the development of effective pro- or anti-angiogenic strategies as required during ischemia or cancer, but also as a novel target for non-angiogenic therapeutic strategies.

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