Stem Cell Applications in Multiple Sclerosis
Thursday, April 27, 2006
Organizers: Juan Lafaille and James Salzer, New York University School of Medicine
5:00 pm – 7:00 pm: Presentations
Steven Goldman, University of Rochester Medical Center, "Therapeutic Remylenation by Human Glial Progenitor Cells."
Mark Freedman, The Ottawa Hospital, University of Ottawa, "Treatment of Advancing Multiple Sclerosis With Immunoablation and Autologous Stem Cell Transplantation: Evidence for Disease Arrest and Potential for CNS Recovery."
"Therapeutic Remylenation by Human Glial Progenitor Cells"
In the adult human forebrain, neural stem cells persist within the ventricular subependyma and give rise to a variety of lineage-biased progenitor phenotypes. These include ventricular zone neuronal progenitor cells, hippocampal neuronal progenitors, and glial progenitors of the parenchyma. Each of these cell types exists within a local niche that tightly regulates both its mitotic activity and lineal derivatives. Within these niches, both neuronal and glial progenitor cells may reside as transit amplifying pools, by which lineage-biased progenitors expand to replenish discrete phenotypes. The largest such pool in the adult brain appears to be that of parenchymal glial progenitors, which comprise as many as three to four percent of all cells in the adult human white matter. These cells can effectively generate myelinating oligodendrocytes in lysolecithin-demyelinated recipient white matter, in both rat and monkey hosts. Moreover, when isolated and transplanted into neonatal shiverer mice, whose brains lack myelin basic protein, these cells can mediate quantitatively substantial and geographically extensive myelination in the recipient brains. Adult progenitors myelinate more efficiently and rapidly than their fetal counterparts, yet fetal progenitors disperse more widely and engraft in greater numbers, suggesting the applicability of these two distinct phenotypes in different disease targets. Remarkably, whereas adult glial progenitors generate only oligodendrocytes and astrocytes within the normal white matter, upon removal from the tissue environment they give rise to neurons as well as glia. Yet even though these cells can act as multipotential progenitors, their in vitro life-span is finite; they typically senesce after three to four months in vitro, and do not express detectable telomerase activity. Thus, parenchymal glial progenitors appear to reside as tissue-specified multipotential progenitors, rather than as residual neural stem cells. By isolating these cells and assessing their patterns of differential gene expression relative to the white matter from which they derive, we have identified a set of signaling pathways that define their homeostatic self-renewal in vivo. This presentation will focus on the use of glial progenitor cells as transplant vectors for the correction of both congenital and acquired demyelination. It will also discuss the molecular interactions of human glial progenitors with the white matter environment, emphasizing those signaling pathways whose perturbation can induce oligodendrocytic differentiation and how this information be used to potentiate myelination from endogenous progenitors in vivo.