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Promising Therapeutic Effects of Embryonic Stem Cells-Origin Mesenchymal Stem Cells in Experimental Pulmonary Fibrosis Models: Immunomodulatory and Anti-Apoptotic Mechanisms

  • Hanna Lee (Department of Internal Medicine, Gyeongsang National University Changwon Hospital) ;
  • Ok-Yi Jeong (Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital) ;
  • Hee Jin Park (Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital) ;
  • Sung-Lim Lee (College of Veterinary Medicine and Research Institute of Life Sciences, Gyeongsang National University) ;
  • Eun-yeong Bok (College of Veterinary Medicine and Research Institute of Life Sciences, Gyeongsang National University) ;
  • Mingyo Kim (Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital) ;
  • Young Sun Suh (Department of Internal Medicine, Gyeongsang National University Changwon Hospital) ;
  • Yun-Hong Cheon (Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital) ;
  • Hyun-Ok Kim (Department of Internal Medicine, Gyeongsang National University Changwon Hospital) ;
  • Suhee Kim (Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital) ;
  • Sung Hak Chun (Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital) ;
  • Jung Min Park (Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital) ;
  • Young Jin Lee (Cell Therapy Center, Daewoong Pharmaceutical, Co., Ltd.) ;
  • Sang-Il Lee (Department of Internal Medicine and Institute of Medical Science, Gyeongsang National University School of Medicine and Hospital)
  • Received : 2023.10.30
  • Accepted : 2023.12.05
  • Published : 2023.12.31
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Abstract

Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DWMSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.

Keywords

Acknowledgement

This study was supported by grants from the Korea Health Technology R&D project through the Korea Health Industry Development Institute, funded by the Korean Ministry of Health and Welfare (HI14C1277) and from the National Research Foundation of Korea (NRF-2020R1I1A3071922) funded by the Korean government (http://www.nrf.re.kr/index).

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