| Central nervous system disorders (CNS) mainly including cerebrovascular diseases (intracerebral hemorrhage and intracerebral ischemsia), neural degenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc), seriously threaten peoples'life. The neruological function and brain struction are difficult to recover from injury because neurons can not regenergate. At present, there are no ideal therapeutic methods for those disorders which affect the life quality of patients seriously. Stem cell therapy is a promsing treatment for neulogical disorders.MSCs exist in connective tissue and the interstitium of organ all over the body and maily reside in bone marrow, which belong to mesodermal multipotent stem cells. MSCs are readily obtained, can be expanded rapidly in vitro, and have low immunogenicity. The MSCs derived from bone marrow were called bone marrow derived-MSCs (BMSCs). MSCs become an attractive candidate for cell therapy and tissue engineering since MSCs were reported that can differentiated into neural cells in the brain. hBMSCs used in this experiment derived from healthy male bone marrow, were confimed having the ablity of multi-directional differentiation. Beacuse hBMSCs can be easily obtained, quickly amplificated ex vivo, autoplastic transplanted, induce immune tolerance, relieve or inhibit graft-versus-host diseases, hBMSCs was widely used in the preclinical or clinical research in nerve system disease, autoimmune diseases or blood diseases.The routes of stem cell adminsteration mainly include intracerebral injection, veno-or arterio-injection, abdominal cavity injection and cerebrospinal fluid injection. MSCs reached to brain lesions need time and the onset time was later by the indirectly routes. On the contary, intracerebral injection has many advantages. It has been reported that there were no obvius side effects when MSCs form homogeneity transplanted into the variant brain. How about the safety of intracerebral injection? Can hBMSCs migrate into the brain? Can MSCs differentiate into neural cells? What's the routes and mechanism of migration of hBMSCs if hBMSCs can migrate throughout the brain? So, the safety evaluation of hBMSCs engraftment, the distribution and differentiation of hBMSCs are very important and critical. Small animals (Wistar rats) and non-human primate animals (Macaca Fascicularis) were used to evaluate the safety of intracerebral injection, and engraftment, distribution and differentiation of transplanted-hBMSCs and its migrated mechanisms in the CNS. The transplanted cells were traced by detecting male DNA and labeling in vivo. Double immunofluorescence staining was used to observe the differentiation of hBMSCs. We also detected the mRNA level of neurophins, cytokines, and adhesion molecules by real-time PCR and immunohistochemical staining.Our results indicated that no inflammatory reaction and immunological rejection was detected, and negeneration and necrosis of neural cells were absent in the local injection sites. The transplanted hBMSCs survived, and migrated into the brain after 2 and 4 weeks transplantation. Although hBMSCs were injected unilaterally, male DNA was detected in both brain hemispheres and its distribution was overlapping between transplant recipients. Male DNA also tended to extend rostrally into the forebrain as a function of time posttransplantation, although the difference between 2 and 4 weeks posttransplant was not statistically significant. In rats, hBMSCs migrated along the asllosum-external capsule to the opposite side. We also observed tranlplanted hBMSCs tended to migrate toward vascular and ependymal layer, which may suggest one migratory route of hBSMCs.We also observed transplanted-hBMSCs expressed neuron maker (NeuN) and glial cell maker (GFAP) rather than neural stem cell marker (Nestin). In addtion, the mRNA levels of parts of neurotrophins and growth factors tended to upregulate. Therefore, we speculated that neurotrophins and growth factors might paly great roles in survival and differentiation of stem cells. The expression of N-cadherin increased too after hBMSCs transplantation. N-cadherin plays great roles in migration of neural cells during the devopment of CNS. So, N-cadherin may be one chemotatic factor for hBMSCs' migration. Human UCMSCs were used to detect the role of N-cadherin in stem cells' migration. The results demonstrated that N-cadherin induced the migration of hUCMSCs and increased the expression of endogenous N-cadherin andβ-catenin of hUCMSCs. N-cadherin/β-catenin signalling pathway may paly a role in migration of stem cells.In conclusion, intracerebral transplantation is safe in four weeks. And hBMSCs can migrate into the brain and differentiate into neural cells. The upregulated expression of neurotrophins, growth factors, and N-cadherin in response to hMSCs transplantion may be one mechanism of migration. Objective To investigate the role of IL-10 in treatment of cynomolgus macaques brain ischemia by human bone marrow-derived msenchymal stem cell (hBMSCs) transplantation.Methods A non-human primate ischemia model was used to test the hypothesis that transplanted human bone-marrow-derived MSCs (hBMSCs) exert a neuroprotective effects on cerebral ischemia and upregulate IL-10 expression. We also assessed neuronal apoptosis and astroglial activity in the area around the ischemic lesion and proliferating cells in thesubventricular zone (SVZ).Results Results showed that hBMSC transplantation in ischemic tissues improved the neurological functions and induced an increase in IL-10 expression. In addition, neuronal apoptosis and astroglial activity in the peri-ischemic area decreased, and the number of proliferating cells in the SVZ increased.Conclusion hBMSC transplantation does greatly help the repair of ischemic injury in cynomolgus macaques and the effectiveness of treatment may be associated with the increase of anti2inflammary factor IL-10. |
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