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Single Nuclei Sequencing Reveals Novel Insights Into the Regulation of Cellular Signatures in Children With Dilated
Luka Nicin1,2,3, Wesley T Abplanalp1,2,3, Anne Schänzer4
1Institute for Cardiovascular Regeneration (L.N., W.T.A., D.J., H.M., L.T., S.D.), Goethe University, Germany.
Insights
Pediatric dilated cardiomyopathy (DCM) shows age-dependent cellular changes. Infants with DCM have proregenerative heart cells, while older children exhibit increased fibrosis and activated fibroblasts.
Area of Science:
- Cardiovascular Biology
- Pediatric Cardiology
- Molecular Genetics
Background:
- Dilated cardiomyopathy (DCM) is a primary cause of pediatric heart failure with variable treatment outcomes.
- Lack of large cohort studies hinders progress in pediatric heart failure management.
- Personalized therapy considering age- and disease-specific factors is crucial for improving outcomes.
Purpose of the Study:
- To identify cellular signatures in pediatric DCM using single nuclei RNA sequencing.
- To investigate age-dependent molecular and cellular alterations in pediatric DCM hearts.
Main Methods:
- Single nuclei RNA sequencing was performed on heart tissues from six pediatric DCM patients (ages 0.5-13 years).
- Unsupervised clustering identified 14 distinct cell clusters, representing 6 major cell types.
- Histological analysis and cardiac magnetic resonance imaging (MRI) were used for validation.
Main Results:
- Fibroblast populations increased with age in DCM patients, correlating with cardiac fibrosis.
- Fibroblasts in older DCM patients (>6 years) displayed altered gene expression, including collagen and proteoglycan modulation.
- Infants with DCM possessed a proregenerative cardiomyocyte population, absent in older children, with high expression of cell cycle and metabolic genes.
Conclusions:
- Pediatric DCM exhibits significant age-dependent changes in fibroblast and cardiomyocyte gene expression.
- Infants with DCM show less fibrosis and more proregenerative cellular signatures compared to older children.
- These findings offer novel insights into DCM pathophysiology and potential therapeutic targets.
Background:
Dilated cardiomyopathy (DCM) is a leading cause of death in children with heart failure. The outcome of pediatric heart failure treatment is inconsistent, and large cohort studies are lacking. Progress may be achieved through personalized therapy that takes age- and disease-related pathophysiology, pathology, and molecular fingerprints into account. We present single nuclei RNA sequencing from pediatric patients with DCM as the next step in identifying cellular signatures.
Methods:
We performed single nuclei RNA sequencing with heart tissues from 6 children with DCM with an age of 0.5, 0.75, 5, 6, 12, and 13 years. Unsupervised clustering of 18 211 nuclei led to the identification of 14 distinct clusters with 6 major cell types.
Results:
The number of nuclei in fibroblast clusters increased with age in patients with DCM, a finding that was confirmed by histological analysis and was consistent with an age-related increase in cardiac fibrosis quantified by cardiac magnetic resonance imaging. Fibroblasts of patients with DCM >6 years of age showed a profoundly altered gene expression pattern with enrichment of genes encoding fibrillary collagens, modulation of proteoglycans, switch in thrombospondin isoforms, and signatures of fibroblast activation. In addition, a population of cardiomyocytes with a high proregenerative profile was identified in infant patients with DCM but was absent in children >6 years of age. This cluster showed high expression of cell cycle activators such as cyclin D family members, increased glycolytic metabolism and antioxidative genes, and alterations in ß-adrenergic signaling genes.
Conclusions:
Novel insights into the cellular transcriptomes of hearts from pediatric patients with DCM provide remarkable age-dependent changes in the expression patterns of fibroblast and cardiomyocyte genes with less fibrotic but enriched proregenerative signatures in infants.
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