Novel Insights into the Regulation of Cellular Signatures in Children with Dilated Cardiomyopathy

Objectives: Dilated cardiomyopathy (DCM) is a severe disorder in pediatric patients. The pathological mechanisms underlying DCM in children are poorly understood. We present single nuclei RNA sequencing from pediatric DCM patients as the next step in identifying cellular signatures leading to heart failure.

Methods: We processed heart tissue from 17 children with DCM. Six probes were chosen from children with an age of 0.5 to 13 years for single-cell sequencing. Unsupervised clustering of 18,211 nuclei led to the identification of 14 distinct clusters with six major cell types. The number of nuclei in fibroblast clusters was increased in elderly children. Histological analysis confirmed an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging in 65 children. Fibroblasts of DCM patients over 6 years of age further showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, switch in thrombospondin isoforms, modulation of proteoglycans, and signatures of fibroblast activation. Additionally, a population of cardiomyocytes with a high proregenerative profile was identified in infant DCM patients. This cluster showed high expression of cell cycle activators such as cyclin-D family members, increased glycolytic metabolism and antioxidative genes.

Conclusion: Novel insights into the cellular transcriptomes of hearts from pediatric DCM patients provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.

Publication History

Article published online:
21 February 2021