Fatemeh Pourrajab, Seyed Hosain Hekmatimoghadam & Seyed Khalil Forouzannia
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that BMSCs, microglial and myocardial cells also express TLRs. Toll-like receptors (TLRs) are a group of transmembrane proteins which play critical roles in immune responses. The ligand-mediated stimulation of TLRs family can induce apoptosis of microglial, myocardial and endothelial cells (47). Alternatively, other studies have observed that LPS, an agonist of TLR4, protects myocytes and human dendritic cells from apoptosis through a NF-kB-dependent PI3K/Akt pathway (48). Reports reveal that LPS protect MSCs from oxidative stress-induced apoptosis and enhance proliferation of MSCs via TLR4 and PI3K/Akt pathway (48). Conclusively, stress-stimulated secretion of a variety of growth factors and cytokines by BMSCs, markedly change the pattern of microinviroment cytokine release, all of which accompanied by a genetic reprogramming and molecular switching.
BMSCS BEHAVIOR FOR RECONSTITUTION OF HYPOXIC MICRO-VASCULAR In ischemic cerebrovascular disease, the injury of brain microvascular endothelial cells (BMEC) induces the opening of the brain barrier border (BBB), which leads to a brain edema and nerve damage. Then, the recovery and neogenesis of ischemic penumbral microvasculature is a key point in the retrieval of injured cells (49). BMSCs have become the recent focus of intense research in the treatment of ischemic disease due to their ability to repair and rebuilt of injured microvasculature. Data indicate that under hypoxia BMECs induce BMSCs to differentiate into endothelial cells, whereas BMSCs enhance proliferation and migration of BMECs, and simultaneously increasing the permeability of the BMEC monolayer, presumably through paracrine function (50). Following an injury, there are significantly increased numbers of BMSCs in peripheral blood and at the disrupted site of the injured subjects (51), this trend correlates with significantly increased concentrations of the cytokines VEGF and G-CSF, suggestive of a molecular mechanism for BMSCs mobilization, recruitment and homing (20). BMSC homing to the site of injury involves the arrest within the vasculature and transendothelial migration followed by chemotaxis at the injured tissue. While arresting in the proper vascular position, BMSCs secrete proteases such as MMPs, and be capable of breaking down the endothelial basement membrane and journeying presumably toward chemotactic agents (20, 26). In terms of the second, however, the collagen matrix is essential for the efficient homing. The putative proteases released into collagen I or collagen IV matrices produce proteolytic fragments for attracting more BMSCs toward the site of injury where the medium is a result of stress (25, 26, 52). MMPs are a family of zinc-dependent proteases and classically described in the context of extracellular matrix remodeling under physiological and pathophysiological conditions. They are very important for BMSCs recruitment, migration and differentiation. High-levels of MMPs can enhance angiogenesis in hypoxic conditions. MMP-9 known as Gelatinase B, for example plays an important role in the migration of BMSCs and capable of degrading type IV collagen (a key component of basement membranes) and gelatin. Both, VEGF and MMP-9 can increase vascular permeability (20).