Adult stem cells for neuronal repair.

Abstract

Stem cell research offers great hope to patients suffering from neuronal damage. Stem cell-based regenerative medicine holds huge potential to provide a true cure for patients affected by a neurodegenerative disease or who have suffered a stroke. A stem cell possesses two distinct traits that define it: selfrenewal and differentiation capacity. Self-renewal is the process whereby a single cell gives rise to two daughter cells – one being identical to the original cell and the other further com mitted towards a more restricted phenotype. In turn, the further committed progenitor cell, upon specific cues and signals, may proceed and differentiate to a mature cell type, a process termed differentiation. The stem cell population is comprised of two main cell types: embryonic stem cells and adult stem cells. The first are derived from the early blastocyte and are well known for their pluripo tency, the ability to differentiate into virtually any specific cell type in the adult organism. The latter have been known for years for their capacity to differentiate along their lineage of origin (for example, hematopoetic stem cell differentiating into any mature blood cell type). However, there have been recent reports of the adult stem cell’s ability to differentiate along different lineages than its original organ, showing multipotency and crossing lin eages in a phenomenon known as “trans-differentiation.” The exact mechanism responsible for the beneficial effect of stem cell cellular treatment has yet to be elucidated. In principle there are three different approaches. The first is cell replacement; namely, the direct replacement of the degenerated cells with functional cells, e.g., implantation of differentiated dopaminergic neurons to replace lost cells in the denervated nigrostriatal pathway in patients with Parkinson’s disease. The second approach is neuroprotection, where transplanted stem cells provide environmental support to the affected brain cells by secreting essential cytokines and neurotrophic factors, e.g., intravenous administration of undifferentiated bone marrow stromal cells in the treatment of stroke. The third is gene deliv ery, i.e., stem cells serve as a vehicle to deliver specific supportive genes in the affected area; e.g., implantation of engineered stem cells over-expressing glial-derived neurotrophic factor to the brains of PD patients will protect the remaining unaffected neurons and restrain the onset of the disease. Cellular therapy for PD: clinical trials Parkinson’s disease affects more than 1% of the population over age 60 in the western world. PD is characterized by massive loss of specific dopaminergic neurons in the substantia nigra pars compacta and causes severe motor symptoms. Current treatments for PD comprise mainly dopamine replace ment and symptom alleviation, rather than a cure for the disease. The type specificity of the damaged cells makes PD patients ideal candidates for cellular therapy strategies. Cellbased therapies for PD have until now focused primarily on transplantation of differentiated fetal nigral cells. From the beginning of the last decade, different groups have reported reasonably good results in a series of open label trials [1,2]. Benefits were associated with increased striatal fluorodopa up take and evidence of graft-related dopamine release on positron emission tomography. Postmortem studies demonstrated long graft survival years after transplantation and a significant re-innervation in the patients’ striata. These results encour aged the U.S. National Institutes of Health to sponsor two double-blind trials of fetal nigral tissue transplantation. In one study, Freed and colleagues [3] in Colorado implanted solid grafts of human embryonic mesencephalic cells derived from two donors per side into the striata of advanced PD patients. Despite achieving a modest improvement in motor function in patients under age 60, the study failed to meet its primary endpoint – to improve the quality of life.