Thursday, November 21, 2024
11/21/2024
PROJECT ABSTRACT Idiopathic pulmonary fibrosis (IPF) is an ultimately fatal disease whose only curative treatment is lung transplant. IPF is characterized by formation of fibrotic lesions in the lung, eventually resulting in scarring and progressive loss of lung function. Despite some newer treatments, IPF patients still have a median survival rate of only 3-5 years once diagnosed. Clearly, new therapeutic approaches are needed to treat this devastating disease. A promising avenue of approach is stem cell therapy. In the past 8 years, our lab has been developing lung spheroid cells (LSCs) as a novel source of therapeutic lung cells, and FDA approval of clinical trials with LSC treatment of patients with IPF are being pursued. Nonetheless, stem cell-based therapy faces several important limitations. Live cells need to be carefully preserved and processed before usage, and cell transplantation carries certain immunogenicity and tumorigenicity risks. Importantly, live stem cells cannot be delivered to the lung via inhalation, which is the most convenient and effective route to deliver therapeutics to the lung. Recently, we and others have made the novel and exciting observation that many adult stem cells exert their beneficial effects mainly through secretion of regenerative factors that go on to promote endogenous repair. In the preliminary studies that form the basis for this application, we have discovered that secretions from cultured LSCs are just as, if not more, effective than the LSCs themselves in attenuating and resolving IPF in rodent models of the disease. In the quest for active components in the LSC secretions, we found that LSCs secrete large numbers of exosomes (30-150 nm vesicles secreted by numerous cell types). We have shown that exosomes derived from LSCs (LSC-Exo) are therapeutic and regenerative to the injured lung, suggesting these nanostructures are largely responsible for the reparative response to LSC secretions in rodent models of IPF. It is known that exosomes carry microRNAs (miRs) cargoes that could play important roles in cell-cell communication and tissue repair, and indeed we found that LSC-Exo are highly enriched with miR- 30a and Let-7. In this proposed study, we plan to determine safety and efficacy as well as medium effective dose of LSC-Exo required for lung repair in rodent models of IPF, to determine the major recipient cells of LSC-Exo in the lung, and determine that the relevant molecular target(s) of exosomal mediated repair and recovery. We hypothesize that key miRs withing LSC-Exo such as miR-30a and Let-7 are mediators of the TGF-beta signaling pathway, using the data produced by scRNA-Seq we will finally determine whether further miR enrichment in these exosomes achieves optimal lung repair. The development of cell-free or non-living therapeutics derived from stem cells has the potential to revolutionize current regenerative medicine practice.
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