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Isolation and Functional Characterization of Human Ventricular Cardiomyocytes from Fresh Surgical Samples
Published on: April 21, 2014
Molecular features and cell composition of left-dominant arrhythmogenic cardiomyopathy reveals key pathways and
Yiqi Zhao1, Mengda Xu1, Xiumeng Hua1
1Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, National Centre for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China; Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
Insights
Single-nucleus RNA sequencing reveals increased fibroblasts and adipocytes in left-dominant arrhythmogenic cardiomyopathy (LACM). This study identifies key transcriptional signatures in cardiomyocytes and other cells, offering insights into LACM pathogenesis.
Area of Science:
- Cardiovascular biology
- Genomics
- Molecular medicine
Background:
- Arrhythmogenic cardiomyopathy (ACM) is a heart disorder linked to sudden cardiac death.
- Left-dominant arrhythmogenic cardiomyopathy (LACM) specifically impacts the left ventricle.
- Understanding LACM's cellular and molecular basis is crucial for developing treatments.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms of left-dominant arrhythmogenic cardiomyopathy (LACM).
- To identify key transcriptional signatures and pathways involved in LACM pathogenesis using single-nucleus RNA sequencing (snRNA-seq).
Main Methods:
- Single-nucleus RNA sequencing (snRNA-seq) was performed on heart samples from LACM patients and healthy donors.
- Analysis identified distinct cell populations and differentially expressed genes.
- Immunofluorescence staining validated key molecular findings.
Main Results:
- LACM hearts showed increased fibroblasts and adipocytes in the left ventricle.
- A specific cardiomyocyte subpopulation (CM1) exhibited upregulation of fibrosis, metabolism, and stress markers.
- Fibroblast and adipocyte subpopulations displayed distinct transcriptional profiles related to signaling pathways and cardiac adaptation.
Conclusions:
- This study provides a detailed cellular and molecular map of LACM.
- Identified pathways and transcriptional signatures offer potential therapeutic targets for LACM.
- Enhanced understanding of LACM pathogenesis through advanced sequencing techniques.
Background:
Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by arrhythmias and an increased risk of sudden cardiac death, particularly in left-dominant arrhythmogenic cardiomyopathy (LACM), which primarily affects the left ventricle. This study aims to elucidate the cellular and molecular mechanisms underlying LACM by performing an in-depth single-nucleus RNA sequencing (snRNA-seq) analysis to identify key transcriptional signatures and pathways involved in the disease's pathogenesis.
Method:
Human heart samples were collected from five patients undergoing heart transplantation due to ACM and from four healthy donors. Single nuclei were isolated from myocardial tissues and subjected to snRNA-seq using the 10 × Genomics Chromium platform. Data were processed and analyzed to identify distinct cell populations and their differentially expressed genes. Immunofluorescence staining was used to validate key findings.
Result:
The snRNA-seq analysis revealed an increased proportion of fibroblasts and adipocytes in the left ventricles of LACM patients, suggesting a cellular basis for the fibrofatty remodeling observed in the disease. Key cell populations, including cardiomyocytes (CMs), fibroblasts (Fbs), and adipocytes (Adipo), were identified with distinct transcriptional profiles. We identified a disease-associated cardiomyocyte subpopulation (CM1) characterized by upregulation of fibrosis-, metabolism-, and stress-related markers, indicating transcriptional remodeling processes involved in LACM. The Fb subgroup Fb1 was characterized by genes involved in the PI3K-AKT signaling pathway. Adipocyte subpopulations exhibited gene expression features reflecting adaptation to the cardiac pathological environment, including markers associated with extracellular matrix remodeling and metabolic stress. Immunofluorescence staining validated the high expression of key markers of LACM patients.
Conclusion:
This study provides a cellular and molecular characterization of LACM, identifying key pathways and transcriptional signatures that contribute to the disease's pathogenesis. These findings enhance our understanding of LACM and offer potential targets for therapeutic intervention.
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