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

In a cardiomyocyte hypertrophy model with aberrant Wnt activation, proteomic analysis of extracellular vesicles and transcriptomic profiling reveal a proteostasis signature for early patho-physiological states of cardiomyocytes. Aberrant Wnt activation has been reported in failing cardiomyocytes. Here we present single cell transcriptome profiling of hearts with inducible cardiomyocyte-specific Wnt activation (beta-cat(Delta ex3)) as well as with compensatory and failing hypertrophic remodeling. We show that functional enrichment analysis points to an involvement of extracellular vesicles (EVs) related processes in hearts of beta-cat(Delta ex3) mice. A proteomic analysis of in vivo cardiac derived EVs from beta-cat(Delta ex3) hearts has identified differentially enriched proteins involving 20 S proteasome constitutes, protein quality control (PQC), chaperones and associated cardiac proteins including alpha-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.

Automated summary

In a study on the hypertrophy of cardiomyocytes, it was found that aberrant Wnt activation leads to a proteostasis signature in extracellular vesicles and transcriptomic profiling, indicating early patho-physiological states. Aberrant Wnt activation has been observed in failing cardiomyocytes. Further analysis shows enrichment of extracellular vesicles related processes in hearts with Wnt activation, and the identification of differentially enriched proteins including proteasome constituents, chaperones, and cardiac proteins. These findings suggest that the secretion of extracellular vesicles with a proteostasis signature plays a role in the early adaptation of cardiomyocytes and may have diagnostic and prognostic implications.