YAP-regulated type II alveolar epithelial cell differentiation mediated by human umbilical cord-derived mesenchymal stem cells in acute respiratory distress syndrome

Xiao-Yue Chen; Kuan-Yuan Chen; Po-Hao Feng; Kang-Yun Lee; Yu-Ting Fang; You-Yin Chen; Yu-Chun Lo; Pankaj K Bhavsar; Kian Fan Chung; Hsiao-Chi Chuang

doi:10.1016/j.biopha.2023.114302

YAP-regulated type II alveolar epithelial cell differentiation mediated by human umbilical cord-derived mesenchymal stem cells in acute respiratory distress syndrome

Biomed Pharmacother. 2023 Mar:159:114302. doi: 10.1016/j.biopha.2023.114302. Epub 2023 Jan 25.

Authors

Xiao-Yue Chen¹, Kuan-Yuan Chen², Po-Hao Feng³, Kang-Yun Lee⁴, Yu-Ting Fang⁵, You-Yin Chen⁶, Yu-Chun Lo⁷, Pankaj K Bhavsar⁸, Kian Fan Chung⁹, Hsiao-Chi Chuang¹⁰

Affiliations

¹ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: iryuoscar@gmail.com.
² Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan. Electronic address: 14388@s.tmu.edu.tw.
³ Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: fengpohao@tmu.edu.tw.
⁴ Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: leekangyun@tmu.edu.tw.
⁵ Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address: crosshine@fda.gov.tw.
⁶ Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Industrial Ph.D. Program of Biomedical Science and Engineering, National Yang Ming Chiao Tung University, Taipei, Taiwan. Electronic address: youyin.chen@gmail.com.
⁷ The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. Electronic address: aricalo@tmu.edu.tw.
⁸ National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: p.bhavsar@imperial.ac.uk.
⁹ National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: f.chung@imperial.ac.uk.
¹⁰ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; National Heart and Lung Institute, Imperial College London, London, UK; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: chuanghc@tmu.edu.tw.

PMID: 36701989
DOI: 10.1016/j.biopha.2023.114302

Abstract

Acute respiratory distress syndrome (ARDS) contributes to higher mortality worldwide. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have immunomodulatory and regenerative potential. However, the effects of hUC-MSCs as an ARDS treatment remain unclear. We investigated the role of hUC-MSCs in the differentiation of type II alveolar epithelial cells (AECII) by regulating Yes-associated protein (YAP) in ARDS. Male C57BL/6JNarl mice were intratracheally (i.t.) administered lipopolysaccharide (LPS) to induce an ARDS model, followed by a single intravenous (i.v.) dose of hUC-MSCs. hUC-MSCs improved pulmonary function, decreased inflammation on day 3, and mitigated lung injury by reducing the lung injury score and increasing lung aeration (%) in mice on day 7 (p < 0.05). hUC-MSCs inactivated YAP on AECII and facilitated cell differentiation by decreasing Pro-surfactant protein C (Pro-SPC) and galectin 3 (LGALS3) while increasing podoplanin (T1α) in lungs of mice (p < 0.05). In AECII MLE-12 cells, both coculture with hUC-MSCs after LPS exposure and the YAP inhibitor, verteporfin, reduced Pro-SPC and LGALS3, whereas the YAP inhibitor increased T1α expression (p < 0.05). In conclusion, hUC-MSCs ameliorated lung injury of ARDS and regulated YAP to facilitate AECII differentiation.

Keywords: Alveoli; Inflammation; Pneumocytes; Regeneration; Stem cells.

MeSH terms

Alveolar Epithelial Cells / metabolism
Animals
Cell Differentiation
Galectin 3 / metabolism
Humans
Lipopolysaccharides / metabolism
Lipopolysaccharides / pharmacology
Lung Injury* / metabolism
Male
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stem Cells* / metabolism
Mice
Mice, Inbred C57BL
Respiratory Distress Syndrome* / metabolism
Respiratory Distress Syndrome* / therapy
Umbilical Cord

Substances

Galectin 3
Lipopolysaccharides
YAP1 protein, human