University of Washington (Seattle)
Philip Horner, Ph.D.

Acute Trauma and Control of Stem Cell Gliogenesis

Spinal cord injury sets in motion processes that lead to the formation of a classically described scar which is arguable the strongest impediment to post-injury regeneration. While the molecular and cellular components of the scar are increasingly being elucidated, the early signals that trigger scar formation are unknown. The contribution of mature astrocytes vs. astrocyte progenitor cells to gliosis is surprisingly unclear. Here, we hypothesize that blood extravasation orchestrates the adult spinal cord progenitor (aSCP) response to trauma. Specifically, long lasting effects of blood-derived factors stimulate aSCP to proliferate and restrict their fate to that of astrocytes. In published work and our preliminary data, we provide evidence that endogenous progenitor cells proliferate at 24 hours post-spinal cord injury. In addition we show that components of the coagulation process produce long-lasting restrictions on cellular fate that can be prevented in the presence of the anticoagulant heparin. The present proposal will address the following hypothesis: Post-injury blood extravasation and coagulation induces astrocyte fate restriction of adult spinal cord progenitor cells. We will address this hypothesis by comparing the progenitor response following experimental spinal cord injury in control and heparin treated mice. Aim I will asses the effect of anti-coagulants on progenitor proliferation. Aim II will assess the fate restriction of progenitor cells using mitotic and viral labeling techniques. A better understanding of the initial events that instruct progenitor fate-restriction following spinal trauma will be important for the development of techniques to manipulate the gliosis and support cellular plasticity.

The proposal directly addresses one of the PPAs primary focuses: Understanding the processes involved in the regulation of the neuronal growth. Spinal cord injury introduces cascades that significantly limit regeneration, in particular, the formation of a scar. The present proposal will examine how the initial injury modifies the function of the endogenous stem cells to participate in gliosis and inhibition of regeneration.