Recent studies indicate that cellular derived vesicles can alter the genomic phenotype of separate target cells by transfer of RNA species. Further work has indicated that mesenchymal stem cell-derived vesicles (MSC-dv) can mediate healing of injured renal and marrow tissue by transfer of microRNA. A critical need is to determine whether MSC-dv can be utilized to reverse kidney or marrow damage in humans so afflicted. The present proposal is to define the optimum approach for separating and characterizing MSC-dv carrying "healing" microRNA to renal tissue injured by glycerol exposure or by ischemia/reperfusion or marrow tissue (stem cells) injured by irradiation. The microRNA in "healing" MSC-dv will then be determined by deep sequencing and the specific "healing" microRNA determined by its capacity to be delivered to injured renal and marrow cell line models and restore proliferation and reduce apoptosis. This will be carried out by lipofecting injured cell lines and analyzing proliferation and apoptosis. We will also characterize optimal approaches to loading "healing" MSC-dv with specific "healing" microRNA(s). It is anticipated that these studies will yield the following expected outcomes: 1.) An understanding of the role of micro RNAs in tissue restoration, 2.) a definition of the specific micro RNA or subset of microRNAs responsible for cell fate change and 3.) the development an approach for the delivery of MSC vesicle microRNA to restore injured renal or marrow tissue. This constitutes Stage 1 of the proposal. In Stage 2, after the determination of a "healing" microRNA packaged optimally in MCS-dv for delivery to injured marrow or renal tissue, we next need to optimize delivery schedule for tissue repair, evaluate early and late toxicity, and distribution of the infued agent. In addition, we need to evaluate the stability of "healing" phenotype of the microRNA rich MSC-d vesicles with storage. Optimal healing levels will be assessed in time course experiments where different times and frequencies of infusion are evaluated as to healing effects in our models. During the course of these studies we will also determine early and late toxicities in the infused animals. Total animal organ histology and survival will also be assessed. Next we will track tissue distribution after an optimal infusion schedule and determine the stability of MSC-dv over time under different conditions. The totality of the studies outlined in Stage 1 and 2 are unique and innovative. The delivery of microRNA in MSC-dv to heal tissue injuries is designed to prepare the basis for therapeutic interventions in different renal and marrow diseases which have not been previously attempted.

Public Health Relevance

Extracellular vesicles from mesenchymal stem cells can heal injured kidney and marrow tissues by transferring healing microRNA. We plan to characterize and identify the healing microRNA and engineer extracellular vesicles so that they can contain high levels of this microRNA. This will be used to heal injured marrow and kidney in pre-clinical models.

National Institute of Health (NIH)
National Center for Advancing Translational Sciences (NCATS)
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
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Special Emphasis Panel (ZRG1-OBT-Z (50))
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Tagle, Danilo A
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Rhode Island Hospital
United States
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