PD-L1 and AKT Overexpressing Adipose-Derived Mesenchymal Stem Cells Enhance Myocardial Protection by Upregulating CD25+ T Cells in Acute Myocardial Infarction Rat Model

  • Int J Mol Sci. 2023 Dec 21;25(1):134. doi: 10.3390/ijms25010134.
Yu-Kai Lin  1  2  3 ,  Lien-Cheng Hsiao  1  2  3 ,  Mei-Yao Wu  4  5 ,  Yun-Fang Chen  6 ,  Yen-Nien Lin  1  3 ,  Chia-Ming Chang  2 ,  Wei-Hsin Chung  1 ,  Ke-Wei Chen  1  7 ,  Chiung-Ray Lu  1 ,  Wei-Yu Chen  6 ,  Shih-Sheng Chang  1  3 ,  Woei-Cheang Shyu  7  8  9  10  11 ,  An-Sheng Lee  2  6 ,  Chu-Huang Chen  12  13 ,  Long-Bin Jeng  14  15 ,  Kuan-Cheng Chang  1  2  3
Affiliations
  • 1. Division of Cardiovascular Medicine, China Medical University Hospital, Taichung 404327, Taiwan.
  • 2. Cardiovascular Research Laboratory, China Medical University Hospital, Taichung 404327, Taiwan.
  • 3. School of Medicine, China Medical University, Taichung 404328, Taiwan.
  • 4. School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung 404328, Taiwan.
  • 5. Department of Chinese Medicine, China Medical University Hospital, Taichung 404327, Taiwan.
  • 6. Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan.
  • 7. Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404328, Taiwan.
  • 8. Translational Medicine Research Center, China Medical University Hospital, Taichung 404327, Taiwan.
  • 9. Neuroscience and Brain Disease Center, New Drug Development Center, China Medical University, Taichung 404328, Taiwan.
  • 10. Department of Neurology, China Medical University, Taichung 404328, Taiwan.
  • 11. Department of Occupational Therapy, Asia University, Taichung 413305, Taiwan.
  • 12. Vascular and Medicinal Research, Texas Heart Institute, Houston, TX 77030, USA.
  • 13. New York Heart Research Foundation, Mineola, NY 11514, USA.
  • 14. Cell Therapy Center, China Medical University Hospital, Taichung 404327, Taiwan.
  • 15. Organ Transplantation Center, China Medical University Hospital, Taichung 404327, Taiwan.
PMID: 38203304 DOI: 10.3390/ijms25010134
Abstract

This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure-volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to Reactive Oxygen Species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure-volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25+ regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated Apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries.

Keywords
adipose-derived mesenchymal stem cells (AdMSC); myocardial infarction; programmed death ligand 1 (PD-L1); regulatory T cells.
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