Inhibition of Chondroitin Sulfate Proteoglycan Interactions With Receptor PTPσ Promotes Neurogenesis and Recovery From Stroke

Abstract

Current treatment strategies for stroke primarily focus on reducing the size of ischemic damage and on rescuing dying cells. However, regenerative processes might provide a second target. Neuroregeneration after stroke takes two forms, intrinsic stem cell derived neurons to replace the dead cells and axonal sprouting. Unfortunately, these recuperative efforts are quite inefficient in mammals, leading to only modest improvements in function over time. We have discovered that a major impediment to axon sprouting/regeneration and precursor cell migrations after CNS trauma is a family of potently inhibitory extracellular matrix molecules called chondroitin sulphate proteoglycans. Recently, we have used a small TAT-peptide (Intracellular Sigma Peptide or ISP) that can be administered easily via a systemic route but which enters the CNS to potently and specifically block a major proteoglycan receptor on axons and stem cells (PTPσ) that mediates the inhibition. Utilizing cre mediated inducible gene deletion technology, we have established PTPσ KO adult neural stem cell cultures. We also tested the effects of post-stroke ISP treatment on stroke functional recovery and its influence on neurogenesis and axonal sprouting after stroke. Our results demonstrated that conditional knockout of PTPσ in adult SVZ NSCs has similar effects as ISP peptide inhibition in regulation of adult NSCs neuronal differentiation and migration. In addition, we have also investigated the molecular signaling pathway that might mediate the ISP induced NSCs migration enhancement. Moreover, post-stroke ISP peptide treatment resulted in robust behavioral recovery in an MCAo mouse model, accompanied by extensive axonal sprouting and stem cell migrations into and around the lesion. Transcriptome analyses of peri-lesion cortex at 14 days after stroke in vehicle or ISP treated mice revealed a transcriptional signature of negative regulation of apoptotic pathways and upregulation of axonal development genes. Based on our findings, we propose that CSPGs induced by stroke play a predominant role in the inhibition of neural repair and that blocking CSPG signaling pathways will lead to enhanced neurorepair and functional recovery in stroke.