Immunomodulatory Hydrogels for Stem Cell Therapy after TBI

Duke University, Durham NC

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Abstract

DESCRIPTION (provided by applicant): The center for disease control reports that 1.7 million Americans suffer traumatic brain injuries, half a million of whom are children. Clinical management of traumatic brain injury (TBI) is challenging due to the complexity of the injury as well as due to the paucity of effective treatment options. Due to the complex nature of the injury involving inflammation, cell loss and edema, cell therapies may be necessary as small molecular anti-inflammatory or neuroprotective strategies have not been very successful. Specifically stem cell therapy has the potential to significantly improve outcomes after TBI. However, one major impediment to successful neural stem cell (NSC) therapy is their poor survival after transplantation due to host T cells and Natural Killer (NK) cell mediated apoptosis of transplanted NSCs. Here, we propose to design and engineer in situ gelling hydrogel carriers for NSCs such that they confer immune-privilege for a period of days to weeks in vivo. We propose to exploit the Fas-ligand mediated cell death of T cells and NK cells to generate an immune privilege zone for NSCs. We posit that enhancing NSC survival is a critical and necessary condition to evaluating NSC therapy's potential for treating TBI. Our aims are designed to design the appropriate hydrogel carriers for NSC, test their ability to promote NSC survival in vivo in an experimental model of TBI, and finally investigate whether indeed enhanced NSC survival results in motor and cognitive improvement in a rodent model of TBI relative to untreated cohorts. Successful completion of the proposed studies would have significant impact on improvement of the quality of life of individuals with TBI, and have implications for stem cell therapies in other organ systems.