Exosomes mediated fibrogenesis in dilated cardiomyopathy through a MicroRNA pathway
Xuebin Fu,
Rachana Mishra,
Ling Chen,
Mir Yasir Arfat,
Sudhish Sharma,
Tami Kingsbury,
Muthukumar Gunasekaran,
Progyaparamita Saha,
Charles Hong,
Peixin Yang,
Deqiang Li,
Sunjay Kaushal
Affiliations
Xuebin Fu
Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
Rachana Mishra
Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
Ling Chen
Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
Mir Yasir Arfat
Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
Sudhish Sharma
Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
Tami Kingsbury
Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
Muthukumar Gunasekaran
Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
Progyaparamita Saha
Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA
Charles Hong
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
Peixin Yang
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
Deqiang Li
Department of Surgery, Center for Vascular & Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA; Corresponding author
Sunjay Kaushal
Department of Cardiovascular-Thoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA; Corresponding author
Summary: Cardiac fibrosis is a hallmark in late-stage familial dilated cardiomyopathy (DCM) patients, although the underlying mechanism remains elusive. Cardiac exosomes (Exos) have been reported relating to fibrosis in ischemic cardiomyopathy. Thus, we investigated whether Exos secreted from the familial DCM cardiomyocytes could promote fibrogenesis. Using human iPSCs differentiated cardiomyocytes we isolated Exos of angiotensin II stimulation conditioned media from either DCM or control (CTL) cardiomyocytes. Of interest, cultured cardiac fibroblasts had increased fibrogenesis following exposure to DCM-Exos rather than CTL-Exos. Meanwhile, injecting DCM-Exos into mouse hearts enhanced cardiac fibrosis and impaired cardiac function. Mechanistically, we identified the upregulation of miRNA-218-5p in the DCM-Exos as a critical contributor to fibrogenesis. MiRNA-218-5p activated TGF-β signaling via suppression of TNFAIP3, a master inflammation inhibitor. In conclusion, our results illustrate a profibrotic effect of cardiomyocytes-derived Exos that highlights an additional pathogenesis pathway for cardiac fibrosis in DCM.
