Abstract
Metabolism has emerged as a regulator of core stem cell properties such as proliferation, survival, self-renewal, and multilineage potential. Metabolites serve as secondary messengers, fine-tuning signaling pathways in response to microenvironment alterations. Studies show a role for central metabolite acetyl-CoA in the regulation of chromatin state through changes in histone acetylation. Nevertheless, metabolic regulators of chromatin remodeling in cardiac cells in response to increasing biological age remains unknown. Previously, we identified novel cardiac-derived stem-like cells (CTSCs) that exhibit increased functional properties in the neonatal heart (nCTSC). These cells are linked to a unique metabolism which is altered with CTSC aging (aCTSC). Here, we present an in-depth, RNA-sequencing-based (RNA-Seq) bioinformatic with cluster analysis that details a distinct epigenome present in nCTSCs but not in aCTSCs. Gene Ontology (GO) and pathway enrichment reveal biological processes, including metabolism, gene regulation enriched in nCTSCs, and STRING analysis that identifies a network of genes related to acetyl-CoA that can potentially influence chromatin remodeling. Additional validation by Western blot and qRT-PCR shows increased acetyl-CoA signaling and histone acetylation in nCTSCs compared to aCTSCs. In conclusion, our data reveal that the link between metabolism and histone acetylation in cardiac cells is altered with the aging of the cardiac tissue.
Highlights
Heart disease is characterized by lack of meaningful repair response by the injured cardiac tissue
We describe the identification of novel metabolic modulators of chromatin architecture in cardiac-derived stem-like cells (CTSC), a novel cell type in the heart, through bioinformatic and molecular approaches
cardiac-tissuederived stem-like cell (CTSC) populations—one from 2-day-old neonatal cardiac tissue and one from aged, 2-year-old cardiac tissue as previously described. This was followed by bulk RNA sequencing and detailed bioinformatic-based analyses to understand the transcriptomic profile of each CTSC line (Figure 1A)
Summary
Heart disease is characterized by lack of meaningful repair response by the injured cardiac tissue. Clinical results using several stem cell types have been largely underwhelming [5] and suggest that there is a need for a better understanding of the basic biology of stem cells and their response to injured myocardial environments. We have recently identified a novel cardiac-tissuederived stem-like cell (CTSC) population in the heart which has a unique molecular and cellular profile compared to other known stem cells [6]. CTSCs possess a distinct metabolic phenotype that changes during the transition of the cells from neonatal to aged cardiac tissue concurrent with changes in proliferation and survival, suggesting that cellular metabolism is a mediator of CTSC function. The precise role of metabolic signaling in regulating CTSC molecular and cellular function was not tested and remains unknown
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