Guiding the migration of grafted cells to promote axon regeneration.

Abstract

A promising therapeutic strategy to promote the regeneration of injured axons in the adult central nervous system (CNS) is the transplantation of cells or tissues that can modify the local host environment and support the growth of regenerating axons. Growth-supportive cells that have been successfully used in experimental transplantation therapy of spinal cord injury (SCI) include Schwann cells, mesenchymal stromal cells, olfactory ensheathing cells, genetically modified fibroblasts, and neural stem/progenitor cells (Huang et al., 2010). Cells derived from the embryonic spinal cord and peripheral nerve grafts have been shown to promote the regeneration of injured axons, due largely to the presence of growth-supportive cells such as glial progenitors and Schwann cells, respectively (Cote et al., 2011; Haas and Fischer, 2013). These transplants generate a permissive environment for axon growth by secreting growth factors and forming an adhesive extracellular matrix to overcome the inhibitory environment of the injured tissue. However, the value of these transplants to promote axon regeneration is limited by the fact that most regenerating axons are trapped inside the permissive environment generated by the transplants, failing to grow out of the graft (Figure ​Figure1A,1A, ​,BB) (Haas and Fischer, 2013). While this strategy can be effective for building functional relays via graft-derived neurons (Haas and Fischer, 2014), this approach can not be generalized to other cell types. Therefore, a remaining challenge for therapeutic cell transplantation in CNS injury, in the context of long distance regeneration and connectivity, is to develop strategies to promote axonal growth beyond the graft into putative target areas to form functional synaptic connections. Currently the nature of the “graft trap” of regenerating axons is not fully understood. One possibility is that the regenerating axons stay inside the graft, which expresses much higher levels of attractive guidance factors, i.e., neurotrophic factors, and much lower levels of inhibitory/repulsive factors, i.e., chondroitin sulfate proteoglycan (CSPG), compared to the adjacent host tissue. Another possibility is that although adult CNS axons maintain their growth potential and can regenerate in an optimized environment, their intrinsic growth capability is much lower than axons of embryonic neurons, and thus not suitable for long-distance regeneration. Targeting these mechanisms, several strategies have recently been applied to overcome the “graft trap” in transplantation-based therapy of SCI. One strategy is to further modify host spinal tissue, making the host tissue less inhibitory and thus allowing some of the regenerating axons inside the graft to exit into the host tissue. As an example, Tom et al. (2009) showed that in an experimental model of grafting a peripheral nerve bridge at the site of the injured spinal cord, application of chondroitinase (Chase) at the distal graft/host interface to reduce CSPG-mediated inhibition promoted modest improvement in host-entry of regenerating axons, which would otherwise stop at the distal graft/host junction. Another strategy to promote axonal growth beyond the graft focuses on genetic modification of injured neurons to enhance their intrinsic growth potential using regeneration associated genes (Ma and Willis, 2015). For example, overexpressing the constitutively active form of the Rheb GTPase (downstream of the mTOR pathway) has been shown to enhance the intrinsic growth potential of adult neurons (Wu et al., 2015).