Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling

Aberrant Wnt activation has been reported in failing cardiomyocytes. Researchers at University Medical Center Göttingen present single cell transcriptome profiling of hearts with inducible cardiomyocyte-specific Wnt activation (β-cat^Δex3) as well as with compensatory and failing hypertrophic remodeling. The researchers show that functional enrichment analysis points to an involvement of extracellular vesicles (EVs) related processes in hearts of β-cat^Δex3 mice. A proteomic analysis of in vivo cardiac derived EVs from β-cat^Δex3 hearts has identified differentially enriched proteins involving 20 S proteasome constitutes, protein quality control (PQC), chaperones and associated cardiac proteins including α-Crystallin B (CRYAB) and sarcomeric components. The hypertrophic model confirms that cardiomyocytes reacted with an acute early transcriptional upregulation of exosome biogenesis processes and chaperones transcripts including CRYAB, which is ameliorated in advanced remodeling. Finally, human induced pluripotent stem cells (iPSC)-derived cardiomyocytes subjected to pharmacological Wnt activation recapitulated the increased expression of exosomal markers, CRYAB accumulation and increased PQC signaling. These findings reveal that secretion of EVs with a proteostasis signature contributes to early patho-physiological adaptation of cardiomyocytes, which may serve as a read-out of disease progression and can be used for monitoring cellular remodeling in vivo with a possible diagnostic and prognostic role in the future.

Scheme summarizing the finding in this study

This study revealed an increased EV-cargo secretion including Z-disk proteins prone to misfolding (DES, TNN), proteasome components and chaperone associated proteins by cardiomyocytes upon Wnt activation and pressure overload induced stress. This was accompanied by a concomitant activation of hypoxia response, which is known to activate EV-mediated processes. This response was more accentuated in early compensatory hypertrophic remodeling, suggesting their contribution to hypertrophic disease adaptation, and may overlap with the endosomal autophagic pathway at the formation of amphisomes, also activated upon stress. It is tempting to speculate that increased cellular stress induces protein misfolding, which triggers an excess of ubiquitination and CRYAB-mediated processes activation and the amphisomes are redirected to the exosomal release.