Targeting pro-growth extracellular matrix proteins in the post-stroke brain

Stroke is a devastating neurological condition and the leading cause of lasting motor, sensory and cognitive deficits. These disabilities occur due to the central nervous system’s limited ability to repair itself after injury. Following cortical ischemic stroke, adjacent surviving tissue initiates a limited process of repair characterized in part by axonal sprouting and cortical remodeling. Neurons that undergo axonal sprouting have a unique transcriptional profile, differentially regulating genes in a time and age-specific manner. Among these genes are a number of differentially regulated extracellular matrix proteins, including those that are important in peripheral nervous system regeneration. The extracellular matrix is comprised of a network of proteins that provide support to cells throughout the body. In the central nervous system, the extracellular matrix is implicated in development, ensuring developing axons are guided to the correct destination, modulating signaling pathways that coordinate proliferating cells, and providing a general environment of support. In the mature brain, the extracellular matrix plays key roles in plasticity and support, and undergoes dramatic changes in composition and function following injury. This thesis investigates two differentially regulated extracellular matrix proteins for their ability to induce axonal sprouting and functional recovery following stroke. Matrilin-2 (Matn2) is an adapter protein important for peripheral nerve regeneration but paradoxically is one of the most down-regulated genes in sprouting neurons in young animals. Unique cartilage matrix associated protein (Ucma) is a novel extracellular matrix protein that is one of the most upregulated genes in young animals, but whose expression is almost totally abolished in aged animals following stroke, potentially contributing to the lack of recovery seen as a result of age. Both proteins increased neurite outgrowth in primary neurons, and rescued neurite outgrowth in a stroke-like growth inhibitory environment. Viral overexpression of Matn2 and Ucma revealed that both enhanced axonal sprouting in the post-stroke brain. When assessing ability to enhance functional recovery, Matn2 overexpression accelerated return of motor function to baseline, while Ucma overexpression initially accelerated recovery but only partially restored motor function. Further studies to test translatability of these proteins revealed that restriction of Matn2 adjacent to the injury site still enhanced axonal sprouting, but Ucma overexpression in this context was detrimental to axonal sprouting. In summary, these studies identify novel pro-growth extracellular matrix proteins that enhance axonal sprouting and functional recovery after stroke and identify the pro-growth extracellular matrix as a new target for neural repair after injury