The goal of these proposed “out of box” studies is to develop strategies for mitochondrial transplantation following contusion spinal cord injury (SCI) to deliver normal healthy mitochondria around the injury sites, as well as to identify potential autologous cell sources, in order to prevent secondary tissue injury that is mediated, in large part, by mitochondrial dysfunction and loss. Successful completion of this project will pave the way to treat both acute and potentially chronic stages of SCI, the latter by testing delayed grafting paradigms to extend the therapeutic window of supplementing mitochondria in stage II of this proposal.
The high risk stems from an untested approach that attempts to circumvent traditional cell-mediated transplantation strategies while the high reward lies in the potential to harvest one’s own muscle mitochondria and graft them into the injured spinal cord to promote neuroprotection and regeneration. The PI extensively studied microglial cell transplantation into spinal cord tissue after injury and the Co-I has unique expertise in mitochondrial bioenergetics, notably after SCI. The combined disciplines yielded a logical step forward to branch out into the field of mitochondrial transplantation, notably since it has been applied successfully to different organ pathologies such as cardiac infarction and lung damage.
However, despite numerous cell-grafting approaches being tested both experimentally and in clinical trials for SCI, extensive literature searches reveal that no one has examined whether transplanting exogenous mitochondria is feasible regarding cellular uptake and increases host cellular respiration to promote tissue sparing and/or functional recovery. It is suggested that despite the attrition of grafted stem cells, for example, their transient presence generates a “secretome’ that renders neuroprotection and tissue remodeling. On the contrary, recent compelling studies indicate that such protection is accomplished by mitochondrial transference from graft cells into potentially compromised host cells. Notably, localization of mitochondria within distal branches of sprouting axons is critical for functional regeneration. Accordingly, our novel preliminary data support an approach to inject transgenically-labeled mitochondria into the injured spinal which maintains near normal levels of cellular respiration.
In summary, we propose to evaluate directly the effectiveness of transplanting allogeneic mitochondria versus isogenic, autologous mitochondria isolated from muscles on bioenergetics outcome measures, histopathology and long term behavior. Stage II of this proposal will test delayed grafting paradigms to extend the therapeutic window for supplementing mitochondria in a more chronic model of SCI.
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