| Ischemic brain injury is currently the leading cause of disability and the third-leading cause of death in the developed world. To date, however, no treatment can reverse CNS damage caused by infarction. The recent development of stem cell technologies has raised hopes that functional losses caused by stroke may be regained via stem cell-mediated neuroregeneration. Here we begin with a discussion of neural stem cells both in their normal capacity during embryonic and adult life, as well as their potential regenerative capacity. We then turn specifically to ischemic brain injury, discussing the challenges and opportunities regarding stem cell-mediated therapy for stroke. Among the significant challenges facing the field of neuroregeneration is the development of reliable techniques for following exogenous stem cells after transplantation, as well as endogenous neural stem cells participating in the neurogenic process. We here provide experimental evidence that thymidine analogs, one of the most widely used labels for transplanted cells can be transferred from donor to host cells after transplantation, rendering it an ineffective method for identification of transplanted cells. Therefore, using the transgenic label, GFP, we studied the behavior of several stem cell populations. Of these, MAPCs migrated rapidly to the infarct area, replacing the damaged cortex with MAPC-derived cells by 2 weeks, a finding that was associated with evidence of behavioral recovery. Very few neuronal cells expressing GFP were found, however, and these tended to occur away from the main graft site, in only a small percentage of animals. Longer term studies revealed continued proliferation of the graft area leading to a tumor-like mass at 8 weeks. Mature epithelial structures were observed in some animals suggestive of teratoma-like formation. Exogenous stem cells have been proposed to stimulate endogenous neuroregeneration but few techniques allow lineage tracing of endogenous neural stem cells. We evaluate techniques based on cre/loxP constructs delivered locally via lentivirus, or activated via systemic tamoxifen administration. Together, our studies provide describe the behavior of MAPCs in the CNS, and provide insights into techniques for the study of exogenous and endogenous stem cells. |
