Why the study?
Cardiac fibrosis is a hallmark in late-stage familial DCM, but the underlying mechanisms and whether exosomes secreted from familial DCM cardiomyocytes promote fibrogenesis remain elusive.
Cardiomyocyte-derived exosomes from familial dilated cardiomyopathy promote cardiac fibrosis via miRNA-218-5p, highlighting a novel pathogenic pathway.
Hypothesis-generating for exosome-mediated fibrosis in familial DCM; further validation required before clinical relevance.
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.
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Fu et al. (2023) studied this question.
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