Comparative efficacy and mechanism of action of cardiac progenitor cells after cardiac injury

Muthukumar Gunasekaran; Rachana Mishra; Progyaparamita Saha; David Morales; Wen-Chih Cheng; Arun R Jayaraman; Jessica R Hoffman; Lauran Davidson; Ling Chen; Aakash M Shah; Gregory Bittle; Xuebin Fu; Antariksh Tulshyan; Mohamed Abdullah; Tami Kingsbury; Curt Civin; Peixin Yang; Michael E Davis; Roberto Bolli; Joshua M Hare; Sudhish Sharma; Sunjay Kaushal

doi:10.1016/j.isci.2022.104656

Comparative efficacy and mechanism of action of cardiac progenitor cells after cardiac injury

iScience. 2022 Jun 22;25(8):104656. doi: 10.1016/j.isci.2022.104656. eCollection 2022 Aug 19.

Authors

Muthukumar Gunasekaran¹, Rachana Mishra¹, Progyaparamita Saha¹, David Morales¹, Wen-Chih Cheng², Arun R Jayaraman³, Jessica R Hoffman³, Lauran Davidson¹, Ling Chen¹, Aakash M Shah¹, Gregory Bittle¹, Xuebin Fu¹, Antariksh Tulshyan¹, Mohamed Abdullah^{1

4}, Tami Kingsbury⁵, Curt Civin², Peixin Yang¹, Michael E Davis³, Roberto Bolli⁶, Joshua M Hare⁷, Sudhish Sharma¹, Sunjay Kaushal¹

Affiliations

¹ Departments of Surgery and Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, 225 E. Chicago Avenue, Chicago, IL 60611, USA.
² Center for Stem Cell Biology and Regenerative Medicine, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³ Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, 1760 Haygood Drive, W200, Atlanta, GA 30322, USA.
⁴ Department of Cardiothoracic Surgery, Cairo University, Cairo 11553, Egypt.
⁵ Center for Stem Cell Biology and Regenerative Medicine, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁶ Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.
⁷ University of Miami, Miller School of Medicine, Miami, FL, USA.

Abstract

Successful cell therapy requires cells to resist the hostile ischemic myocardium, be retained to continue secreting cardioprotective growth factors/exosomes, and resist immunological host responses. Clinically relevant stem/progenitor cells in a rodent model of acute myocardial infarction (MI) demonstrated that neonatal cardiac mesenchymal stromal cells (nMSCs) provide the most robust cardiac functional recovery. Transplanted nMSCs significantly increased the number of tissue reparative macrophages and regulatory T-cells and decreased monocyte-derived inflammatory macrophages and neutrophils in the host myocardium. mRNA microarray and single-cell analyses combined with targeted depletion studies established CD47 in nMSCs as a key molecule responsible for cell retention in the myocardium through an antiphagocytic mechanism regulated by miR34a-5p. Gain and loss-of-function studies demonstrated that miR34a-5p also regulated the production of exosomes and cardioprotective paracrine factors in the nMSC secretome. In conclusion, miR34a-5p and CD47 play an important role in determining the composition of nMSCs' secretome and immune evasion, respectively.

Keywords: Cell biology; Molecular biology; Molecular medicine; Stem cells research.

Grants and funding

R01 HL118491/HL/NHLBI NIH HHS/United States