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.

The Marginal Zone/Layer I as a Novel Niche for Neurogenesis and Gliogenesis in Developing Cerebral Cortex

“…Indeed, we also found that cells isolated from all the regions of the cortical parenchyma at early postnatal (P8) stages generate primary neurospheres, in accordance with our BrdU labeling at this stage (supplemental Fig. 3, available at www.jneurosci.org as supplemental material) and previous data in the literature (Marmur et al, 1998;Belachew et al, 2003). However, although we detect slowly dividing cells in the adult cortex, no neurospheres can be derived any longer from the cortical parenchyma, including the layer 1 (data not shown).…”

Analysis of Stem Cell Lineage Progression in the Neonatal Subventricular Zone Identifies EGFR+/NG2− Cells as Transit-Amplifying Precursors

“…Despite being downregulated after birth, PSANCAM remains elevated in neurogenic areas [34] and has been used to isolate from various brain regions highly proliferative precursors displaying multipotency in vitro [36,37] and in vivo [38]. In particular, Marmur et al found that in the postnatal cortex all multipotent precursors are PSANCAM þ , whereas in the SVZ the multipotent cells equally consist of PSANCAM À and PSANCAM þ precursors.…”

Autocrine/Paracrine Activation of the GABAAReceptor Inhibits the Proliferation of Neurogenic Polysialylated Neural Cell Adhesion Molecule-Positive (PSA-NCAM+) Precursor Cells from Postnatal Striatum

“…Although they are already restricted to either a glial (Trotter et al, 1989;Grinspan and Franceschini, 1995;Ben Hur et al, 1998;Vitry et al, 1999) or a neuronal (Mayer-Proschel et al, 1997) preferential fate, cultured PSA-NCAM ϩ progenitors preserve a relative degree of pluripotentiality (Marmur et al, 1998;Vitry et al, 2001). Considering that PSA-NCAM ϩ cells can be neatly used for brain repair purposes (Keirstead et al, 1999;Vitry et al, 2001), there is much interest in studying signaling factors that regulate their development.…”