Combined delivery of chondroitinase ABC and human induced pluripotent stem cell-derived neuroepithelial cells promote tissue repair in an animal model of spinal cord injury

The lack of tissue regeneration after traumatic spinal cord injury in animal models is largely attributed to the local inhibitory microenvironment. To overcome this inhibitory environment while promoting tissue regeneration, we investigated the combined delivery of chondroitinase ABC (chABC) with human induced pluripotent stem cell-derived neuroepithelial stem cells (NESCs). ChABC was delivered to the injured spinal cord at the site of injury by affinity release from a crosslinked methylcellulose (MC) hydrogel by injection into the intrathecal space. NESCs were distributed in a hydrogel comprised of hyaluronan and MC and injected into the spinal cord tissue both rostral and caudal to the site of injury. Cell transplantation led to reduced cavity formation, but did not improve motor function. While few surviving cells were found 2 weeks post injury, the majority of live cells were neurons, with only few astrocytes, oligodendrocytes, and progenitor cells. At 9 weeks post injury, there were more progenitor cells and a more even distribution of cell types compared to those at 2 weeks post injury, suggesting preferential survival and differentiation. Interestingly, animals that received cells and chABC had more neurons than animals that received cells alone, suggesting that chABC influenced the injury environment such that neuronal differentiation or survival was favoured.We thank Mr Peter Poon for performing spinal cord injuries and helping with behavioural testing. We thank Dr AndreaMothe for helpful advice and discussions, Dr Malgosia Ip for help with material synthesis and chondroitinase ABC expression, and Mr Bartlomiej Maracewicz for help with image analysis. We are grateful to funding from the Craig H Neilsen Foundation (Grant to MSS and AN), the Canadian Institutes of Health Research (Foundation grant to MSS), and the Natural Sciences and Engineering Research Council of Canada (Discovery grant toMSS and CGSM to PA)