TY - JOUR
T1 - Ratio of miRNA-29 to miRNA-199 expression coordinates mesenchymal stem cell repair of bleomycin-induced pulmonary injury
AU - Elliot, Sharon J.
AU - Anderson-Terhune, Dustin
AU - Roos, Benjamin
AU - Rubio, Gustavo A.
AU - Xia, Xiaomei
AU - Pereira-Simon, Simone
AU - Catanuto, Paola
AU - Civettini, Gina
AU - Hagen, Emily S.
AU - Arvanitis, Constadina
AU - Shahzeidi, Shahriar
AU - Glassberg, Marilyn K.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/3/11
Y1 - 2025/3/11
N2 - Our previous work demonstrated the anti-fibrotic effects of infusion of adipose-derived mesenchymal stem cells (ASCs) to prevent or repair bleomycin (BLM)-induced lung injury. The present study investigates mechanisms driving these anti-fibrotic effects. Pulmonary fibrosis developed at day 12 in 22-month-old C57BL/6 male mice after intratracheal BLM instillation. There was a decrease in indices of pulmonary fibrosis, including collagen content, AKT activation, collagen types I and III, αV-integrin, tumor necrosis factor alpha, and transforming growth factor β mRNA after infusion of ASCs 12 days post-BLM treatment compared to BLM alone. Infusion of ASCs increased the population of alveolar types I and II epithelial cells that had been reduced after BLM treatment. miRNAscope technology and reverse-transcription polymerase chain reaction revealed that ASC-treated mice demonstrated increased miR-29a, decreased miR-199, and increased telomere length, telomerase RNA component, and telomerase reverse transcriptase compared to BLM alone. In vitro and ex vivo experiments using double-transfected mouse or human myofibroblasts (miR-29 mimic, and miR-199 inhibitor) confirmed that alterations of these miRNAs regulate downstream effectors of fibrosis. These data suggest that alteration of the ratio of anti-fibrotic to fibrotic miRNAs and increase in telomere length are critical mechanisms of ASC-mediated repair of BLM-induced pulmonary fibrosis.
AB - Our previous work demonstrated the anti-fibrotic effects of infusion of adipose-derived mesenchymal stem cells (ASCs) to prevent or repair bleomycin (BLM)-induced lung injury. The present study investigates mechanisms driving these anti-fibrotic effects. Pulmonary fibrosis developed at day 12 in 22-month-old C57BL/6 male mice after intratracheal BLM instillation. There was a decrease in indices of pulmonary fibrosis, including collagen content, AKT activation, collagen types I and III, αV-integrin, tumor necrosis factor alpha, and transforming growth factor β mRNA after infusion of ASCs 12 days post-BLM treatment compared to BLM alone. Infusion of ASCs increased the population of alveolar types I and II epithelial cells that had been reduced after BLM treatment. miRNAscope technology and reverse-transcription polymerase chain reaction revealed that ASC-treated mice demonstrated increased miR-29a, decreased miR-199, and increased telomere length, telomerase RNA component, and telomerase reverse transcriptase compared to BLM alone. In vitro and ex vivo experiments using double-transfected mouse or human myofibroblasts (miR-29 mimic, and miR-199 inhibitor) confirmed that alterations of these miRNAs regulate downstream effectors of fibrosis. These data suggest that alteration of the ratio of anti-fibrotic to fibrotic miRNAs and increase in telomere length are critical mechanisms of ASC-mediated repair of BLM-induced pulmonary fibrosis.
KW - MT: Non-coding RNAs
KW - mechanisms
KW - mesenchymal stem cells
KW - microRNA
KW - pulmonary fibrosis
KW - telomeres
UR - https://www.scopus.com/pages/publications/86000163550
UR - https://www.scopus.com/inward/citedby.url?scp=86000163550&partnerID=8YFLogxK
U2 - 10.1016/j.omtn.2025.102461
DO - 10.1016/j.omtn.2025.102461
M3 - Article
AN - SCOPUS:86000163550
SN - 2162-2531
VL - 36
JO - Molecular Therapy Nucleic Acids
JF - Molecular Therapy Nucleic Acids
IS - 1
M1 - 102461
ER -