2. Academic Validation
  3. Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes

Every road leads to Rome: therapeutic effect and mechanism of the extracellular vesicles of human embryonic stem cell-derived immune and matrix regulatory cells administered to mouse models of pulmonary fibrosis through different routes

  • Stem Cell Res Ther. 2022 Apr 12;13(1):163. doi: 10.1186/s13287-022-02839-7.
Shengnan Yang  # 1 2 3 4,  Peipei Liu  # 2 3 4 5,  Tingting Gao  # 6 7 8,  Dingyun Song 2 3 4,  Xinyu Zhao 1 2 3 4,  Yupeng Li 1 2 3 4,  Jun Wu 6 7 8 9,  Liu Wang 6 7 8 9 10,  Zai Wang 11,  Jie Hao 12 13 14 15 16,  Chen Wang 17 18 19 20 21,  Huaping Dai 22 23 24
Affiliations

Affiliations

  • 1 Harbin Medical University, Harbin, 150081, Heilongjiang Province, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China.
  • 3 National Center for Respiratory Medicine, Beijing, 100029, China.
  • 4 Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China.
  • 5 Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
  • 6 National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100190, China.
  • 7 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
  • 8 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
  • 9 Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
  • 10 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 11 Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, 100029, China. [email protected].
  • 12 National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, 100190, China. [email protected].
  • 13 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 14 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 15 Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China. [email protected].
  • 16 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 17 Harbin Medical University, Harbin, 150081, Heilongjiang Province, China. [email protected].
  • 18 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China. [email protected].
  • 19 National Center for Respiratory Medicine, Beijing, 100029, China. [email protected].
  • 20 Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China. [email protected].
  • 21 Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China. [email protected].
  • 22 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China. [email protected].
  • 23 National Center for Respiratory Medicine, Beijing, 100029, China. [email protected].
  • 24 Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, 100029, China. [email protected].
  • # Contributed equally.
PMID: 35413874 DOI: 10.1186/s13287-022-02839-7
Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. Whether extracellular vesicles are effective in treating IPF and what is the optimal administrative route is not clear. Our previous studies have shown that immunity and matrix regulatory cells (IMRCs) derived from human embryonic stem cells can safely treat lung injury and fibrosis in mouse models, and its mechanism of action is related to the paracrine effect. In this study, we investigated the therapeutic effects of IMRC-derived extracellular vesicles (IMRC-EVs) on a bleomycin-induced pulmonary fibrosis mouse model and explored the optimal route of administration.

Methods: To study the biodistribution of IMRC-EVs after administration via different routes, NIR labeled-IMRC-EVs were delivered by intratracheal (IT) or intravenous (IV) route, and in vivo imaging was acquired at different time points. The therapeutic effects of IMRC-EVs delivered by different routes were analyzed by assessing histology, lung function, cytokines levels, and transcriptome profiling. RNA-seq of lung tissues was performed to investigate the mechanisms of EV treatment through IT or IV administrations.

Results: IMRC-EVs mainly reserved in the liver and spleen when administrated via IV route; and mainly retained in the lungs via the IT route. IMRC-EVs administrated via both routes demonstrated a therapeutic effect as attenuated pulmonary fibrosis, improved lung function, and histological parameters. Based on our RNA-seq results, different pathways may be affected by IMRC-EVs administrated via IT or IV routes. In addition, in vitro experiments showed that IMRC-EVs inhibited epithelial-to-mesenchymal transition induced by TGF-β.

Conclusion: IMRC-EVs administrated via IT or IV routes generate different biodistributions, but are both effective for the treatment of bleomycin-induced pulmonary fibrosis. The therapeutic mechanisms of IMRC-EVs administrated via different routes may be different.

Keywords

Biodistribution; Extracellular vesicles; Human embryonic stem cells; IMRC; Mesenchymal stem cells; Pulmonary fibrosis; Route of administration.

Figures
Products