Precursor cells and tissue repair paradigms
The third approach, and more conventional application of precursor cells in disease paradigms, is the transplantation of these cells into models of genetic disease or injury of the CNS. Within this context we are studying the usefulness of early glial progenitors in different paradigms: (a) as a means of replacing injured cells, (b) for the stimulation of endogenous repair mechanisms, and (c) to modulate glial scaring.
How GRP-derived astrocytes modulate glial scar formation when transplanted into acute spinal cord lesions is part of a study in collaboration with Drs. Mark Noble, Margot Mayer-Proschel, Jeannette and Stephen Davies (University of Colorado). Initial experiments demonstrate a dramatic effect on various parameters of the scar, including the levels of proteoglycan expression, the ultrastructural organization of the scar, and also in the degree of neurite extension and functional recovery obtained as a consequence of cell transplantation. The effects observed depend on which GRP-derived astrocyte cell type is transplanted. As part of our studies on the mechanisms controlling the differentiation of these separate astrocyte cell types, my lab is focusing on the distinct properties of these astrocytes to determine what may be causing this modification of the scar in situ. Our discovery of signaling molecules that enable the specific generation and expansion of astrocyte precursor cell populations now provides a novel new tool for use in CNS repair. The dramatic effects of GRP-derived astrocytes in spinal cord injury repair raise the question of whether astrocyte-specific progenitor cells will be similarly useful in these regards.
The ability to isolate and study glial lineage cells provides a unique opportunity to investigate molecular disease mechanisms in otherwise intractable neurodegenerative diseases. This also provides a tool to develop new therapeutic strategies, whether through direct transplantation of specialized precursors that have a high probability of generating the desired cell type in situ, or as an in vitro screening system for use in drug development. With a focus on astrocyte and glial biology, we are now extending these studies to include human CNS and embryonic stem cells.
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