Transplantation for stroke

Abstract

Stroke is the most common cause of disability in the United States, and one of the leading causes of mortality and disability in the world. The hope that damage to the CNS can be reversed or at least ameliorated is the central idea behind the research into neural repair. The ultimate repair for the brain should restore the entire lost structure and it's function. However, partial benefit is possible from addressing some of the needs of the injured brain. These partial solutions are the basis of current research into brain repair after stroke. An opportunity arises for two kinds of intervention: (1) replacement of neurons; (2) support of existing neurons, to prevent excessive degeneration and promote rewiring and plasticity. Transplantation for stroke in the rat model was regularly reported starting in 1992, demonstrating graft survival and even evidence of connection with the host brain. These studies determined several parameters for future work in stroke models, but ultimately had limited efficacy and did not progress to clinical experiments. A variety of cell types have been tried for restoration of brain function after stroke, mostly in rodent models. Human fetal cells had shown some promise in clinical studies for the treatment of Parkinson's disease. The technical and ethical difficulties associated with these cells promoted a search for alternatives. These include porcine fetal cells, human cultured stem cells, immortalized cell lines, marrow stromal cells, Sertoli cells pineal cells, and other sources. Human clonal cell lines have few ethical limitations, but some questions remain regarding their safety and efficacy. Autologous somatic stem cells are a very attractive source--there are no ethical concerns and graft rejection is not an issue. However, it is not clear that somatic cells can are plastic enough and can be safely induced to a neural fate. Restorative treatment for stroke is a new field of study. Naturally, new ideas abound and many strategies have been suggested and tried. Methods and controversies abound, and include: local delivery of cells to the area of the stroke versus grafting to an area of the brain far removed form the stroke; cell therapy for reconstitution of structure and function versus use of cell grafts to support intrinsic repair and recovery mechanisms; intravascular administration of bone marrow or other stem cells; and combination grafts, or co-grafting of several cell types or cells and other substances. The various strategies address the issue of restorative treatments form different perspectives. Some interventions occur early after stroke, or are intended to preserve existing neural structures. For example, treatment strategies that aim to provide trophic support may demonstrate early beneficial results. Other strategies aim for growth and integration of new neurons to replace those lost after stroke. In this case, early beneficial results are not likely. Functional integration of grafted neurons, if it can ever happen, is likely to require training and exercise of the appropriate capacities. Further advances in preclinical studies of neural transplantation will require improved animal models with increased sensitivity to subtle behavioral and imaging changes. Non-human primate models have been established and may increase in importance as a phase before clinical trials. The future of brain repair for stroke is likely to require some form of combination therapy designed to replace the lost cells and supporting structure, attract new blood supply, support and enhance intrinsic repair and plasticity mechanisms.