Mechanisms regulating astrogliosis and functional recovery following spinal cord injuryPublic Deposited
The studies in this thesis are directed towards defining the signaling mechanisms that regulate astrogliosis after SCI and towards developing potential therapeutic techniques for modifying this process. The central hypothesis is that alteration of the extracellular milieu after SCI can limit the deleterious effects of glial scar formation and enhance functional recovery. Astrogliosis following SCI has a dual role; one as a mediator of repair and homeostasis and the other as an inhibitor of regeneration. Ideally, therefore, modifying astrogliosis to promote regeneration for therapeutic purposes would require preservation of the beneficial effects of gliosis while reducing its detrimental effects in inhibition of axon outgrowth. In Chapter 2, we show that injection of a nanoengineered bioactive peptide amphiphile (IKVAV-PA) into the injured cord reduces scar progression without affecting astrocytic hypertrophy. Further, there is regeneration of sensory and motor axons and improvement in locomotor function in these animals, indicating that the extracellular environment can be reengineered to modulate astrogliosis and promote axon regeneration. In Chapter 3, we identify the beta1integrin receptor subunit as a key target gene upregulated by IKVAV PA. Beta1 integrin is not expressed by reactive astrocytes following SCI, which is consistent with the finding that the PA does not affect the initial reactive hypertrophy. Instead it prevents astroglial commitment by beta1integrin expressing glial progenitors, thereby reducing the number of astrocytes at the lesion site. In Chapter 4, we investigated the role of BMP signaling in astrogliosis using BMP receptor knock out mice. Conditional ablation of BMPR1a led to deficits in the early reactive hypertrophy, increased infiltration by inflammatory cells and worsened locomotor recovery. Conversely, BMPR1b null mice developed normal reactive astrocytes, had significantly smaller lesion volumes and normal locomotor recovery, and had an attenuated glial scar in the chronic stages following injury. Hence BMP signaling regulates multiple phases of astrogliosis, with BMPR1a and BMPR1b receptors exerting opposing effects on reactive astrocytic hypertrophy. Overall our findings support the hypothesis that targeting specific signaling pathways involved in gliosis can provide a novel therapeutic approach that enhances functional outcomes after SCI.