Glial restricted progenitors are a therapeutic platform for axonal regeneration in spinal cord injury

Christopher James Haas

doi:10.17918/00000836

Spinal cord injury (SCI) is a complex disorder characterized by physical disruption of axonal pathways, resulting in permanent losses in motor, sensory, and autonomic function, and a cascade of secondary inflammatory events resulting in the generation of physical and chemical barrier, the glial scar, which significantly limits axonal regeneration necessary for functional reconnectivity. Astrocyte replacement, particularly through the use of glial restricted progenitors (GRP) is a promising therapeutic strategy that possesses the ability not only to replace lost astrocytes and oligodendrocytes, but also modulate the lesion environment and promote axonal regeneration. The overall goal of this thesis was to highlight the permissive properties of GRP prepared from the fetal CNS or from human embryonic stem cells and develop combinatorial strategies utilizing these permissive cells as a therapeutic platform for the support of long distance regeneration and functional connectivity. Specifically, this project examined the ability of GRP to 1) support long-distance axonal regeneration of two discrete axonal tracts, the ascending dorsal column sensory and the descending corticospinal motor systems and 2) to serve as a therapeutic platform with alternative strategies designed to further modify the extrinsic environment and intrinsic regenerative potential of injured axons. Chapters 2 and 3 demonstrate that GRP, isolated from the fetal rodent or human CNS, or prepared from human embryonic stem cells, can be differentiated into distinct, albeit heterogeneous, populations of astrocytes that retain considerable morphological and phenotypic plasticity. GRP and derived astrocytes supported axonal growth of various neuronal populations in vitro and supported regeneration into grafts following transplantation into acute and chronic rodent SCI. Furthermore, GRP demonstrated a robust ability to modify the SCI micro-environment, limiting immune cell invasion and decreasing the deposition of inhibitory chemical matrices. Chapter 4 builds upon these properties, utilizing GRP as a therapeutic platform in combinatorial strategies directed at the extrinsic environment to facilitate long-distance regeneration beyond the graft. Despite these combinations, axonal regeneration was modest, limited by the poor intrinsic regenerative capacity of adult CNS axons. Modification of the intrinsic regenerative potential of injured axons or the use of a neuronal relay, built upon a GRP platform, was necessary to bridge the graft site, underscoring the permissive properties of GRP.

Glial restricted progenitors are a therapeutic platform for axonal regeneration in spinal cord injury

Files and links (1)

Abstract

Metrics

Details

Glial restricted progenitors are a therapeutic platform for axonal regeneration in spinal cord injury

Files and links (1)

Abstract

Metrics

Details

Drexel University Social media