Sonic hedgehog and neurotrophin-3 increase oligodendrocyte numbers and myelination after spinal cord injury

Abstract

Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. Multiple channel bridges have been investigated as a means to create a permissive environment for regeneration, with channels supporting axonal growth through the injury. Bridges support robust axon growth with myelination of the axons, and herein we investigated the cell types that are myelinating the axons and whether trophic factors can enhance myelination. Lentivirus encoding for neurotrophin-3 (NT3), sonic hedgehog (SHH) and the combination of these factors was delivered from bridges implanted into a lateral hemisection defect at T9/T10 in mice, and the response of endogenous progenitor cells within the spinal cord was investigated. Relative to control, the localized sustained expression of these factors significantly increased growth of regenerating axons into the bridge and enhanced axon myelination 8 weeks after injury. SHH decreased Sox2+ cells and increased Olig2+ cells, whereas NT3 alone or in combination with SHH enhanced GFAP+ and Olig2+ cells relative to control. For delivery of lentivirus encoding for either factor, we identified cells at various stages of differentiation along the oligodendrocyte lineage (e.g., O4+, GalC+). Expression of NT3 enhanced myelination primarily by infiltrating Schwann cells, whereas SHH over-expression substantially increased myelination by oligodendrocytes. Gene delivery represents a promising tool to direct activation and differentiation of endogenous progenitor cells for applications in regenerative medicine.

Neurotrophic Factors Used to Treat Spinal Cord Injury

“…Other axonal populations also respond to exogenous application of NT-3 after SCI (Bradbury et al, 1999;Bradbury, King, Simmons, Priestley, & McMahon, 1998;Hou et al, 2012;Lu et al, 2007;Taylor, Jones, et al, 2006), although in contrast to BDNF, NT-3 has no impact on rubrospinal neurons or their axons (Ruitenberg et al, 2003), and reduced growth of axons from brainstem neurons (Tsai et al, 2006). Positive effects on myelination have been documented (Han et al, 2015;Hwang et al, 2011;Ji et al, 2015;Yang et al, 2015), perhaps associated with infiltrating Schwann cells (Thomas et al, 2014).…”

Engineering Biomaterials to Influence Oligodendroglial Growth, Maturation, and Myelin Production

“…However, in these studies myelination still occurred by Schwann cells rather than oligodendrocytes [Pittier et al, 2005]. Since then, numerous groups have observed myelination from Schwann cells in biomaterials [Gingras et al, 2008;Xiong et al, 2012;Thomas et al, 2014].…”

Injectable Hydrogels for Spinal Cord Repair: A Focus on Swelling and Intraspinal Pressure

“…For example, the single-dose delivery of chondroitinase ABC-encoding lentivirus after contusive SCI results in significant functional improvement [James et al, 2015]. The delivery of genes encoding other therapeutic biomolecules, such as growth factors and anti-inflammatory cytokines, has also been reported to enhance spinal cord regeneration [Tuinstra et al, 2012;Thomas et al, 2014]. Efficient, biomaterial-mediated delivery of genes is less dependent on hydrogel swelling than the delivery of proteins or other small molecules.…”

“…As macroporosity improves the infiltration of host cells through hydrogel implants, the same macroporous architecture can support the migration of transplanted cells into the surrounding tissue and, potentially, their functional integration with the patient's spinal cord. In the case of gene therapies, macroporosity-facilitated cell infiltration can enable more cells to contact genetic vectors, thereby increasing the delivery efficiency [Aviles and Shea, 2011;Shepard et al, 2012;Thomas et al, 2014]. The in situ crosslinking and swelling of hydrogels in irregularly shaped injection sites allows for a more intimate interface with host tissue, where some swelling pressure may actually help keep the implant positioned flush against tissue.…”