Isolation and Developmental Characterization of Cerebral Cortical Multipotent Progenitors

Abstract

Multipotent neural progenitor species present within developing and adult periventricular generative zones can give rise to all of the major cellular elements of the brain. Although lineage specification during development has been thought to be restricted to these generative zones, we have utilized quantitative immunoselection techniques to isolate an enriched population of multipotent neural progenitor cells that express polysialylated neural cell adhesion molecule (PSA-NCAM) from postnatal day 2 cerebral cortex independent of generative zones. This population of cerebral cortical progenitor cells exhibited robust proliferation in response to epidermal growth factor and subsequently gave rise to clonally derived neurons, astrocytes, and oligodendrocytes. Quantitative regional analysis further demonstrated that while the multipotent cells derived from the cerebral cortex uniformly expressed PSA-NCAM, multipotent cells derived from generative zones contained equal proportions of PSA-NCAM-positive and -negative multipotent progenitor cells. The generation of individual cellular lineages from cortical multipotent progenitors could be enhanced by specific cytokines that are expressed within the cerebral cortex. Further, while oligodendroglial progenitor cells derived from cortical multipotent progenitors exhibited responsiveness to platelet-derived growth factor (PDGF) and neurotrophin-3 (NT-3), primary cultures of cortical oligodendroglial progenitors were responsive to PDGF but not to NT-3. These observations suggest that in addition to glial progenitors that commit to a specific lineage prior to migration from generative zones, there is within the cerebral cortex a separate pool of multipotent cells that are capable of generating mature glial progeny in response to specific environmental cues. Therapeutic interventions aimed at differentiation of endogenous cerebral pools of multipotent progenitors may provide a novel strategy for amelioration of the sequelae of environmental and genetic insults to the postnatal cerebrum.