Timothy O`Shea, University of California Los Angeles, Department of Neurobiology, Los Angeles, United States

Bioengineering a CNS glial framework in fibrotic compartments to support neural regeneration

Funded in: 2019, 2020, 2021


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Problem: Damaged neural connections fail to spontaneously regenerate

Target: Transplantation of immature astroglia in chronic SCI

Goal: Investigate ways to re-establish neural tissue at fibrotic lesions sites

 

Traumatic spinal cord injury (SCI) destroys large volumes of neural tissue resulting in termination of ascending and descending neural connectivity across the level of the lesion. These damaged neural connections fail to spontaneously regenerate. Within damaged neural tissue regions, a wound healing response that attempts to minimize the extent of tissue damage results in the formation of a non-neural, fibrotic lesion. This fibrotic lesion is permanently devoid of neural cells and impedes the repair of neural circuits. 

The overall goal of the research is to investigate ways to re-establish neural tissue at these fibrotic lesions sites to support the formation of new, functional neural circuits. To work towards this goal this project tests the transplantation of immature astroglia in chronic SCI. Transplanted immature astroglia can secrete growth factors and provide extracellular substrates that are absent in the fibrotic lesion but that are required to support new neural circuit formation. 

The hypothesis for this project therefore is that reintroducing immature astroglia into chronic SCI will provide critical cellular and molecular support to stimulated regrowing axons (nerve fibres) such that extensive new neural circuits through complete SCI lesions can be formed and maintained. In a chronic complete crush SCI model in the mouse, the team will evaluate whether immature astroglia grafts can provide long-term support to regenerated neural circuits and whether these transplanted cells aid in encouraging other host glia to migrate into fibrotic lesions. 

This project leverages: (i) previously validated biomaterial carriers that support the survival, differentiation and integration of cell grafts; (ii) reporter mouse lines to identify host glia; and (iii) recently reported methods to stimulate regrowth of axons. Overall, this work provides new knowledge regarding cell transplantation in chronic SCI as well as insight into graft cell phenotypes that provide long-term support of regenerated neural circuits in SCI.