A Novel Growth-Promoting Pathway Formed by GDNF-Overexpressing Schwann Cells Promotes Propriospinal Axonal Regeneration, Synapse Formation, and Partial Recovery of Function after Spinal Cord Injury

Abstract

Descending propriospinal neurons (DPSN) are known to establish functional relays for supraspinal signals, and they display a greater growth response after injury than do the long projecting axons. However, their regenerative response is still deficient due to their failure to depart from growth supportive cellular transplants back into the host spinal cord, which contains numerous impediments to axon growth. Here we report the construction of a continuous growth-promoting pathway in adult rats, formed by grafted Schwann cells (SCs) overexpressing glial cell line-derived neurotrophic factor (GDNF). We demonstrate that such a growth-promoting pathway, extending from the axonal cut ends to the site of innervation in the distal spinal cord, promoted regeneration of DPSN axons through and beyond the lesion gap of a spinal cord hemisection. Within the distal host spinal cord, regenerated DPSN axons formed synapses with host neurons leading to the restoration of action potentials and partial recovery of function.

c-Jun Gene-Modified Schwann Cells: Upregulating Multiple Neurotrophic Factors and Promoting Neurite Outgrowth

“…3 In addition, genetically modified SCs that overexpress a single type of NF, including BDNF, NGF, GDNF, or NT-3, are even more effective than nonmodified SCs for promoting neuronal survival and axonal regeneration. 29,32,34,35 Recently, an increasing number of studies have shown that co-delivery of multiple NFs holds greater therapeutic promise than the delivery of a single factor. 4,22 However, the simultaneous upregulation of multiple NFs remains a great challenge.…”

Cell biology of spinal cord injury and repair

“…(BDNF), neurotrophin-3 (NT3), glia-derived neurotrophic factor (GDNF), and others, which are not detectably produced in the lesions, will promote injured axon regrowth in an axon-selective manner (19,88,89). Such findings highlight the importance of the absence of required chemoattractive molecules in the failure of spontaneous axon regeneration after CNS injury.…”

“…Various means of reactivating neuron-intrinsic growth programs are emerging, including modulating specific genetic pathways ( Figure 3A and discussed above), providing neuronal cell bodies with specific growth factors (150) or inflammatory factors (51,55,151), or stimulating neuronal activity (152). There is a growing list of chemoattractive growth factors that stimulate and guide regrowth of specific axons after SCI, including BDNF and NT3 for sensory axons (19,88), GDNF for propriospinal axons (89), and IGF1 for corticospinal axons (153), as well as pleotropic growth factors such as FGF and EGF that act in beneficial but undefined ways (154)(155)(156). Modulating axonal cytoskeleton may improve growth cone formation and axon regeneration (38,157,158).…”

“…Without glia, neuronal elements are unlikely to persist. Neuroglial cell grafts that can support host axon regrowth include Schwann cells (89,161,163) and astroglia (59)(60)(61). Coaxing of axons to regrow past grafts into spared host tissue and form connections can be facilitated by chemoattractive growth factors (88).…”

Role of Autologous Bone Marrow Mononuclear Cells in Chronic Cervical Spinal Cord Injury-A Longterm Follow Up Study

“…Cellular transplantation is one of the promising options currently being explored to reverse the damage. Preclinical studies have suggested that a variety of cells such as bone marrow cells, [5] olfactory ensheathing cells, [6] Schwann cells, [7] macrophages, [8] and neural progenitor cells [9] encourage functional recovery in SCI patients.…”