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Principal Investigator: Phuong-Uyen C Dinh
Organization: NORTH CAROLINA STATE UNIVERSITY RALEIGH
Fiscal Year: 2024
Award: $368,788
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Allogenic><Apoptosis><Apoptosis Pathway><Autologous><Bleo><Bleomycin><Bone-Derived Transforming Growth Factor><COVID associated ARDS><COVID associated acute respiratory distress syndrome><COVID induced ARDS><COVID induced acute respiratory distress syndrome><COVID related ARDS><COVID related acute respiratory distress syndrome><COVID-19 associated ARDS><COVID-19 associated acute respiratory distress syndrome><COVID-19 induced ARDS><COVID-19 induced acute respiratory distress syndrome><COVID-19 related ARDS><COVID-19 related acute respiratory distress syndrome><COVID-19/ARDS><COVID-19/acute respiratory distress syndrome><COVID/ARDS><COVID/acute respiratory distress syndrome><COVID19 associated ARDS><COVID19 associated acute respiratory distress syndrome><COVID19 induced ARDS><COVID19 induced acute respiratory distress syndrome><COVID19 related ARDS><COVID19 related acute respiratory distress syndrome><COVID19/ARDS><COVID19/acute respiratory distress syndrome><Cell Body><Cell Communication><Cell Interaction><Cell Therapy><Cell Transplantation><Cell secretion><Cell-to-Cell Interaction><Cells><Cellular Secretion><Cicatrix><Clinical><Clinical Trials><Common Rat Strains><Connective Tissue><Coupled><Data><Development><Diagnosis><Disease><Disease Progression><Disorder><Dose><Down-Regulation><Electroporation><Face><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Fibrotic lesions in lung><Future><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genes><Genomic approach><Infiltration><Infusion><Infusion procedures><Inhalation><Inhaling><Label><Lung><Lung Grafting><Lung Respiratory System><Lung Tissue Fibrosis><Lung Transplantation><Lung damage><Lung scar><Lung tissue scar><Macrophage><Maps><Mediating><Mediator><Micro RNA><MicroRNAs><Milk Growth Factor><Modeling><Molecular><Molecular Target><Mφ><Nanostructures><Network Analysis><Ontology><Pathway Analysis><Pathway interactions><Patients><Platelet Transforming Growth Factor><Play><Population><Process><Progenitor Cells><Programmed Cell Death><Pulmonary Fibrosis><Pulmonary Graft><Pulmonary Scar><Pulmonary Tissue fibrosis><Pulmonary Transplant><Pulmonary Transplantation><Rat><Rats Mammals><Rattus><Recombinant Proteins><Recovery><Regenerative Medicine><Resolution><Risk><Rodent Model><Role><Route><SARS-CoV-2 associated ARDS><SARS-CoV-2 associated acute respiratory distress syndrome><SARS-CoV-2 induced ARDS><SARS-CoV-2 induced acute respiratory distress syndrome><SARS-CoV-2 related ARDS><SARS-CoV-2 related acute respiratory distress syndrome><SARS-CoV-2/ARDS><SARS-CoV-2/acute respiratory distress syndrome><Safety><Scarring at the lung><Scarring in the lung><Scars><Severities><Severity of illness><Short interfering RNA><Single cell seq><Small Interfering RNA><Source><Survival Rate><TGF B><TGF Beta Signaling Pathway><TGF-beta><TGF-β><TGF-β Signaling Pathway><TGFbeta><TGFβ><Testing><Therapeutic><Therapeutic Effect><Transcript Expression Analyses><Transcript Expression Analysis><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Tumorigenicity><Vesicle><Visualization><Work><adult progenitor><adult stem cell><analyze gene expression><antifibrotic agent><antifibrotic medication><antifibrotic therapy><antifibrotic treatment><cell mediated therapies><cell type><cell-based therapeutic><cell-based therapy><cellular targeting><cellular therapeutic><cellular therapy><cellular transplant><clinical translation><clinically translatable><coronavirus disease 2019 associated ARDS><coronavirus disease 2019 associated acute respiratory distress syndrome><coronavirus disease 2019 induced ARDS><coronavirus disease 2019 induced acute respiratory distress syndrome><coronavirus disease 2019 related ARDS><coronavirus disease 2019 related acute respiratory distress syndrome><coronavirus disease 2019/ARDS><coronavirus disease 2019/acute respiratory distress syndrome><coronavirus disease associated ARDS><coronavirus 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