Cell therapy: replacement.

Abstract

Not long ago, the ability of the brain to restore function through regeneration of neural elements was thought to be nonexistent. It is now known that not only does some regenerative capacity exist, but implanted cells can integrate into the host brain, survive, and reverse neurological deficits. Neural stem cells, fetal transplants, immortalized cell lines, and bone marrow stromal cells show promise in experimental models of neurological disease including stroke. Although it is clear that transplanted cells function, the mechanism by which neurological deficits might improve is less certain. Transplanted cells may preserve existing host cells and connections through secretion of trophic factors; establish local connections that enhance synaptic activity; provide a bridge for host axonal regeneration; or actually replace cellular elements. Several observations from animal and human studies of cell therapy support the possibility that transplanted cells exert at least some of their effect through cellular replacement. In the early stages of brain development, implanting neural stem cells leads to replacement of multiple cellular elements including neurons and glia.1 Thus, the potential for cell replacement exists, but whether it persists into adulthood is uncertain. Models of Parkinson’s disease (PD) provide the most direct support for cell replacement as an important effect of cell therapy. Fetal ventral mesencephalic neurons grafted into the striatum in animal models of PD restore dopamine levels and improve function.2 Similar grafts outside the striatum fail to achieve clinical benefit. In humans, such fetal grafts produce clinical benefit 3 that accrues gradually rather than immediately, suggesting an accumulation of synaptic connections that eventually results in sufficient dopaminergic transmission to improve neurological deficits. Autopsy findings in patients receiving fetal grafts demonstrate implanted cell survival as well as axon growth and synaptic connections4. Additional support comes from