Mesenchymal Stem Cell Derived Extracellular Vesicles for Traumatic Brain Injury

Texas A&M University Health Science Ctr, College Station TX

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Abstract

Project Summary The goal of the proposed studies is to develop an efficient human mesenchymal stem cell (hMSC)-derived extracellular vesicle (EV) therapy for improving brain function in both acute and chronic phases after a traumatic brain injury (TBI). Studies in the previous funding period showed that a single intranasal (IN) administration of hMSC-EVs 90 minutes after TBI leads to better brain function. Such effects were associated with the inhibition of the nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome-p38 mitogen-activated protein kinase (p38/MAPK) pathway and better hippocampal neurogenesis. This renewal application proposes studies on the efficacy of hMSC-EVs with delayed administration in the acute phase or administration in the chronic phase after a TBI. Additional studies will identify highly enriched miRNAs mediating robust antiinflammatory effects within the hMSC-EVs cargo and test hMSC-EVs loaded with specific miRNAs for their ability to mediate robust therapeutic effects in the chronic phase of TBI. Specific Aim 1 studies will investigate whether delayed IN administrations of hMSC-EVs in the acute phase of TBI would lead to better cognitive and mood function by restraining the progression of acute neuroinflammation into a chronic state and maintaining better hippocampal neurogenesis. hMSC-EVs will be administered to young adult mice 4 or 24 hours post-TBI when acute neuroinflammatory and neurodegenerative processes are active. To understand mechanisms, the studies will also test hMSC-EVs with a knockdown of select antiinflammatory miRNAs that are highly enriched in their cargo. Specific Aim 2 studies will examine whether IN administrations of hMSC-EVs in the chronic phase after TBI would improve cognitive and mood function by modulating chronic neuroinflammation. hMSC-EVs will be given to young adult mice one-month post-TBI when chronic neuroinflammation and cognitive and mood impairments are already present. Specific Aim 3 studies will analyze whether loading select miRNAs into hMSC-EVs cargo enhances their antiinflammatory effects and promotes better cognitive and mood function when administered in the chronic phase after a TBI. Individual miRNAs with antiinflammatory properties (miR-30e-3p, miR-let-7c-5p, miR-20b-5p, miR-24-3p) will be loaded into hMSC-EVs and administered to young adult mice one-month post-TBI. In all Specific Aims, the studies will rigorously measure hMSC-EVs administration-mediated effects on the transcriptomic signature of activated microglia and reactive astrocytes via single-cell RNA sequencing, the activation of chronic NLRP3-p38/MAPK and cyclic GMP-AMP synthase (cGAS)-the stimulator of interferon genes (STING) signaling pathways via molecular assays, hippocampal neurogenesis, and cognitive and mood function. The proposed translational research studies are highly relevant to developing an allogeneic, off-the-shelf, hMSC-EV therapy in acute and chronic phases after a TBI.