Intracerebral Stem Cell Transplantation In Experimental Stroke Models

Cerebral ischemia causes severe functional deficits leaving majority of patients with permanent disabilities. Physical rehabilitation remains the only widely accessible therapy that facilitates functional recovery. Stem cells are suggested to possess the ability to replace lost cells and tissue and thus may enhance functional recovery after stroke. Indeed, according to previous studies stem cells moderately facilitated recovery in animal models of stroke. We used rat models of focal cerebral ischemia and intracerebral transplantation of stem cells. Cells were injected into close proximity of the injured brain tissue one week after the stroke. The animals were tested in sensorimotor tests in various timepoints to quantify functional recovery. We transplanted neurospheres isolated from subventricular zone (SVZ) of mice or human neuronal progenitor cells (hNPC) derived from human embryonic stem cells (hESC). Survival, migration and differentiation of stem cells were examined using immunohistochemistry, immunofluorescence techniques, stereology and confocal microscopy. In addition, the effects of enriched environment (EE) rehabilitation and running exercise combined with stem cell therapy were examined. Animals received immunosuppressive drug to minimize rejection of the transplants. Results show that the combination therapy of rehabilitation and SVZ stem cell transplantation resulted into enhanced migration of stem cells and better functional outcome within first weeks after the ischemic insult. Longterm studies of SVZ cells revealed that the majority of transplanted cells disappeared after the first month and the remaining cells differentiated into glial cells within two and three months after the transplantation. Transplantation of hESC-derived hNPCs resulted into modest functional recovery. Again the survival of cells was minimal. Majority of hNPCs expressed precursor marker nestin, however some of the cells had neuronal phenotypes two months after the transplantation. In longterm studies the EE rehabilitation had no effect on the transplanted SVZ/hNPC cells. We found sustained activation of immune cells in the brains that had received cell transplantation. In conclusion, stem cell therapy supports endogenous brain repair mechanisms during the first weeks after transplantation, and EE rehabilitation supports the beneficial effects of stem cells. However, the cells fail to survive for protracted time periods after intracerebral transplantation. It is crucial to identify the factors restricting stem cell survival and migration in stroke injured cerebral microenvironment before the true effects of transplantation therapy can be measured. National Library of Medicine Classification: WL 355; WL 354; QU 325; QU 328; QY 58; QY 60.R6 Medical Subject Headings: Brain; Brain Ischemia; Stroke; Stem Cells; Embryonic Stem Cells; Rehabilitation; Running; Recovery of Function; Disease Models, Animal; Rats; Mice, Transgenic; Cell Transplantation; Stem Cell Transplantation; Cell Survival; Cell Movement; Cell Differentiation; Cell Death; Graft Rejection; Cerebral Ventricles; Green Fluorescent Proteins; Nerve Tissue Proteins; Immunohistochemistry; Fluorescent Antibody Technique; Microscopy, Confocal