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Recombinant Human Bone Morphogenetic Protein-2 Priming of Mesenchymal Stem Cells Ameliorate Acute Lung Injury by Inducing Regulatory T Cells

  • Jooyeon Lee (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Jimin Jang (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Sang-Ryul Cha (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Se Bi Lee (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University) ;
  • Seok-Ho Hong (Department of Internal Medicine, School of Medicine, Kangwon National University) ;
  • Han-Sol Bae (Cellular Therapeutics Team, Daewoong Pharmaceutical) ;
  • Young Jin Lee (Cellular Therapeutics Team, Daewoong Pharmaceutical) ;
  • Se-Ran Yang (Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kangwon National University)
  • Received : 2023.09.18
  • Accepted : 2023.12.11
  • Published : 2023.12.31
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Abstract

Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSCBMP2) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSCBMP2 were associated with migration and growth. MSCBMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSCBMP2. MSCBMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3+CD25+ Treg of CD4+ cells were further increased in ALI mice treated with MSCBMP2. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSCBMP2. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSCBMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2017M3A9B4051542, 2020R1A2C2010712, 2020R1A5A8019180 and 2022M3A9E4016936, RS-2023-00225239), Particulate Matter Management Specialized Graduate Program through the Korea Environmental Industry & Technology Institute(KEITI) funded by the Ministry of Environment(MOE) and Daewoong Pharmaceutical (120210855).

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