Lineage Restriction and the Astroglial Cell Fate
Although the exact mechanisms of progressive lineage restriction of stem cells and progenitor cells in the CNS remain largely unknown, it is clear that lineage-restricted progenitor cells are the real work-horses of organogenesis and tissue building. Stem cells in contrast, function as a source of the lineage-restricted progenitor cells and only in the earliest stages of development do they constitute a numerically significant population in any tissue. Consequently understanding the signals that control the proliferation and lineage decisions of restricted progenitors, will be essential to understanding tissue formation and repair.
Based on our studies of Vanishing White Matter leukodystrophy and collaborative studies of spinal cord injury paradigms, we have become increasingly interested in the importance and heterogeneity of astrocytes. Astrocytes have been studied in specific developmental and disease paradigms, and while GFAP continues to be the most frequently employed defining marker of astrocytes, it is clear that phenotypes can vary dramatically between astrocytes found during development, in acute lesions and in glial scar tissue.
My laboratory has taken a two-pronged approach towards studying the generation of astrocytes: (a) the micro-array based analysis of astrocyte differentiation and (b) the systematic development of a library of markers that can be used to identify and purify distinct neural cell populations, including astrocyte progenitors and different astrocytic sub-populations. In both cases we have taken advantage of our ability to generate enriched populations of two distinct types of astrocytes from glial restricted progenitor (GRP) cells. These astrocyte populations, referred to as GRP-Derived Astrocyte type 1 (GDA1) and type-2 (GDA2) astrocytes, differ in multiple properties including their morphology, marker expression and in their ability to support neurite outgrowth. Some have likened GDA1 astrocytes to astrocytes found during normal development, while GDA2 have been suggested to resemble reactive astrocytes formed in response to numerous CNS insults.
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