Oligodendrocyte progenitor molecular biology

Regulation of adult human oligodendrocyte progenitor cell fate

We have previously assessed the cell biology and transplantation characteristics of adult human oligodendrocyte progenitor cells (Nunes et al., 2003; Roy et al., 1999; Windrem et al., 2004; Windrem et al., 2002). Furthermore, we have established means for their specific isolation, using CNP2:GFP and A2B5 based fluorescence-activated cell sorting (FACS), and then assessed their lineage potential (Nunes et al., 2003; Roy et al., 1999). We discovered that when removed to low density culture, the progenitors were multipotential, and gave rise to neurons as well as to glia (Nunes et al., 2003). Thus, absent autocrine and paracrine influences on their differentiation, adult WMPCs were not restricted to oligodendrocytic fate. To assess the role of the tissue environment in regulating progenitor fate, we then investigated gene expression by adult human WMPCs. We focused on identifying those transcripts that are differentially expressed by the WMPC, relative to its local tissue environment. This process enabled us to predict ligand-receptor interactions that maintain the progenitor state, as well as those that determine whether a given cell develops into an astrocyte, oligodendrocyte, or neuron. This analysis has identified a set of parallel pathways that together appear to regulate the maintenance, mobilization and differentiated fate of parenchymal progenitor cells. We are currently exploring the use of a combination of protein delivery, adenoviral overexpression and lentiviral RNAi knock-down to evaluate the individual elements of these candidate systems. By this means, we intend to better define the niche for gliogenesis in the adult human white matter, and by so doing to establish both necessary and sufficient genetic targets for directing the phenotypes generated by resident progenitor cells.

References

Nunes MC, Roy NS, Keyoung HM, Goodman RR, McKhann G, Jiang L, et al. Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat.Med. 2003; 9: 439.

Roy NS, Wang S, Harrison-Restelli C, Benraiss A, Fraser RA, Gravel M, et al. Identification, isolation, and promoter-defined separation of mitotic oligodendrocyte progenitor cells from the adult human subcortical white matter. J Neurosci 1999; 19: 9986.

Windrem MS, Nunes MC, Rashbaum WK, Schwartz TH, Goodman RA, McKhann G, et al. Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat.Med. 2004; 10: 93.

Windrem MS, Roy NS, Wang J, Nunes M, Benraiss A, Goodman R, et al. Progenitor cells derived from the adult human subcortical white matter disperse and differentiate as oligodendrocytes within demyelinated lesions of the rat brain. Journal Of Neuroscience Research 2002; 69: 966.

Currently funded by NIH: 2R01NS039559-05, Berlex Biosciences, NMSS TR 3762-A-1