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

Abstract

Aberrant Wnt activation has been reported in failing cardiomyocytes. Here we present single cell transcriptome profiling of hearts with inducible cardiomyocyte-specific Wnt activation (β-catΔex3) 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 β-catΔex3 mice. A proteomic analysis of in vivo cardiac derived EVs from β-catΔex3 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.

Single cell sequencing revealed the mechanism of CRYAB in glioma and its diagnostic and prognostic value

“…For example, research has shown that increased levels of CRYAB in glioblastoma patients are closely related to decreased survival rates and increased susceptibility to metastatic diseases. The expression of the CRYAB gene has been identified as a prospective diagnostic indicator for a range of cancers, including prostate cancer, colorectal cancer, and gastric cancer ( 65 ). The assessment of CRYAB gene expression levels offers valuable insights into the prognosis and treatment response of various tumors.…”

Hypoxia and TNF-alpha modulate extracellular vesicle release from human induced pluripotent stem cell-derived cardiomyocytes

“…hiPSC-CMs are increasingly recognized as a relevant in vitro model to study human cardiomyocyte biology. In addiZon, these cells release EVs 12,13,15,19,[40][41][42][43][44][45][46] , although the variaZons in the heterogeneity of these EVs remain unclear. The protocol applied here 47 enabled the generaZon of a pure populaZon of beaZng cardiomyocytes (Figure S1, Video S1).…”

A new "single" era of biomedicine and implications in disease research

“…These independent or combined "single" technologies have helped us not only to create a high-resolution SC type map of human tissues [127] and three-dimensional nuclear architecture, gene expression, and epigenetic modifications, [128] but also to assess and analyze immune cell differentiation, [129,130] to uncover cellular and molecular mechanisms and to discover new therapeutic targets for human diseases, [49,[131][132][133] in particular COVID-19 and CVDs, as well as to trace cancer progression. [134] It can be said that this is indeed a new "single" era of biomedicine and its current implications and research in both CVDs and COVID-19 [135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150] as well as others will definitely open a new beautiful future.…”