Cardiomyocyte-fibroblast interaction regulates ferroptosis and fibrosis after myocardial injury
Mary E. Mohr,
Shuang Li,
Allison M. Trouten,
Rebecca A. Stairley,
Patrick L. Roddy,
Chun Liu,
Min Zhang,
Henry M. Sucov,
Ge Tao
Affiliations
Mary E. Mohr
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
Shuang Li
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
Allison M. Trouten
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
Rebecca A. Stairley
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
Patrick L. Roddy
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
Chun Liu
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Min Zhang
Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
Henry M. Sucov
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC 29425, USA
Ge Tao
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA; Corresponding author
Summary: Neonatal mouse hearts have transient renewal capacity, which is lost in juvenile and adult stages. In neonatal mouse hearts, myocardial infarction (MI) causes an initial loss of cardiomyocytes. However, it is unclear which type of regulated cell death (RCD) occurs in stressed cardiomyocytes. In the current studies, we induced MI in neonatal and juvenile mouse hearts and showed that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrated that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine effects and direct cell-cell interaction. CFs show strong resistance to ferroptosis due to high ferritin expression. The fibrogenic activity of CFs, typically considered detrimental to heart function, is negatively regulated by paired-like homeodomain 2 (Pitx2) signaling from cardiomyocytes. In addition, Pitx2 prevents ferroptosis in cardiomyocytes by regulating ferroptotic genes. Understanding the regulatory mechanisms of cardiomyocyte survival and death can identify potentially translatable therapeutic strategies for MI.
