Each year approximately 12,000-20,000 individuals receive a spinal cord injury (SCI), usually resulting in permanent paralysis for which there are currently no successful clinical therapeutics or interventions. This lack of recovery is largely attributable to the loss of neurons and oligodendrocytes (OLs) following SCI, which results in axon degeneration and demyelination, respectively. But while OLs are post-mitotic and cannot self- renew, they can be replaced through differentiation of an endogenous progenitor population known as NG2 cells. NG2 cells form a non-overlapping cellular network encompassing the entire CNS, and they respond rapidly to CNS trauma by proliferating, migrating to the injury site, and contributing to remyelination. However, only a portion of proliferating NG2 cells differentiate into OLs following injury or demyelination; what other functions these remaining cells sub-serve in tissue repair and what regulates their responses are largely unknown. Therefore, this proposal will investigate the `non-progenitor' role of NG2 cells following CNS injury and the idea that NG2 cells are necessary for limiting tissue loss. In particular, we will determine the consequences on SCI tissue integrity and repair if NG2 cells are (1) deleted, (2) impaired by inactivation of key signaling mechanisms, or (3) challenged with a second injury.
Aim 1 will investigate the role of proliferating NG2 cells in glial scar formation and tissue repair after SCI using a thymidine kinase/ganciclovir model to achieve cell ablation in transgenic mice. Experiments in Aim 2 will resolve the roles of STAT3 signaling in NG2 cells and how this pathway contributes to their participation in proliferation, differentiation, and glia scar formation after SCI. Finally, Aim 3 will build upon our novel preliminary data which suggest that factors in the SCI environment impair the ability of NG2 cells to properly respond to secondary demyelination. Experiments for Aim 3 will employ a hemicontusive SCI model in rats followed by subsequent challenge with chemical demyelination to determine the post-SCI duration of NG2 cell impairment. Together the Aims presented in this proposal seek to elucidate a novel reparative role of NG2 cells following SCI and signaling mechanisms involved in the induction of their response to injury. This knowledge will help to build the basis for novel therapeutic strategies in SCI and other traumatic and demyelinating disorders.
Spinal cord injury is a devastating trauma for which there are currently no clinical therapies. This research seeks to understand the role of spinal cord progenitor cells after injury and how they contribute to recovery and repair. Through this work we will gain a deeper knowledge of how these cells are affected by injury, providing novel targets and strategies for future therapeutic investigations.
| Hesp, Zoe C; Yoseph, Rim Y; Suzuki, Ryusuke et al. (2018) Proliferating NG2-Cell-Dependent Angiogenesis and Scar Formation Alter Axon Growth and Functional Recovery After Spinal Cord Injury in Mice. J Neurosci 38:1366-1382 |
