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Cell therapy in the regeneration of central nervous system injuries: transplantation of bone marrow stem cells expressing chondroitinase AC

Abstract

Traumas caused to the brain and to the spinal cord lead to severe and irreversible deficiencies due to the poor regenerative ability of the central nervous system (CNS), contrary to what happens to the peripheral nervous system (PNS). The estimated mortality by cranioencephalic trauma, at population level, is 26 to 39/100.000 inhabitants. Treatment is based in physiotherapy and there is a slight improvement, although there are no drugs available to repair injuries caused to the spinal cord or brain. Studies about SNC injury and regeneration are fundamental to the comprehension of the degeneration process as well as to the development of future treatments. Injuries to the CNS, caused either by traumas or pathologies, result in a glial reaction, eventually leading to the formation of glial scar. At the injury site, glial cells secrete factors that are inhibitory to axonal outgrowth, consequently blocking neuronal regeneration. Besides that, remielinization of the axons is also inhibited. The glial response to the injury recruits oligodendrocytes precursors, astrocytes, meningeal cells and microglia, which will constitute the glial scar. At least four molecules, produced by oligodendrocytes, present axonal outgrowth inhibitory activity: 1) MAG (myelin-associated glycoprotein), 2) OMgp (Oligodendrocyte Myelin glycoprotein) and 3) Nogo, all plasma membrane proteins that interact with NgR (Nogo receptor) e p75 (p75 nerve growth factor receptor), and 4) Chondroitin Sulfate Proteoglycans (CSPG). Data in the literature show that all glial cell types produce CSPG in response to neuronal injury. Besides the increase in the amount of CSPG expressed, chondroitin sulfate structure seems to be altered at the glial scar. It has been observed that chondroitin 6-sulfated expressed by axonal regeneration inhibitory cells but not by permissive cells, indicating a possible role of 6-sulfation in the inhibitory activity of chondroitin sulfate. Several data suggest that the carbohydrate moiety of the proteoglycan, i.e. chondroitin sulfate, is responsible for the inhibitory activity. Degradation of chondroitin sulfate chains by specific enzymes, named chondroitinases, reduces the inhibitory activity of CSPGs. Both in vitro and in vivo treatments with chondroitinase ABC, an enzyme that degrades the sugar moiety of the CSPG without altering the core protein, lead to axonal outgrowth. Regarding cell therapy, the adult CNS is able to incorporate stem or progenitor cells transplanted to the injury site or near it. The stem cells can be originated from embryo or adult tissues and transplantation can promote functional recovery of the injuried area. There are reports in the literature about stem cell incorporation into the CNS, and several reports demonstrate that adult bone marrow stem cells, both in humans and rodents, can be incorporated into the tissue where they are transplanted and, in most cases, they express genes and perform functions of the cells from that given tissue. This project aims to combine the use of adult mesenquimal stem cells with chondroitin sulfate degradation by chondroitinase AC in the regeneration of CNS injuries, transplanting stem cells transfected with a vetor bearing chodroitinase AC gene. In this way, we hope to contribute to the development of more efficient treatments for CNS injuries. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FILIPPO, THAIS R. M.; GALINDO, LAYLA T.; BARNABE, GABRIELA F.; ARIZA, CAROLINA B.; MELLO, LUIZ E.; JULIANO, MARIA A.; JULIANO, LUIZ; PORCIONATTO, MARIMELIA A.. CXCL12 N-terminal end is sufficient to induce chemotaxis and proliferation of neural stem/progenitor cells. STEM CELL RESEARCH, v. 11, n. 2, p. 913-925, . (12/00652-5, 05/04061-8)

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