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Single-Cell Reconstruction of Progression Trajectory Reveals Intervention Principles in Pathological Cardiac
Zongna Ren1,2, Peng Yu1, Dandan Li1
1State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (Z.R., P.Y., D.L., Z.L., Y.L., Y.W., B.Z., L.W.).
Insights
This study reveals dynamic cell crosstalk in pathological cardiac hypertrophy, identifying macrophage activation as a key target. Interventions targeting specific cell types and stages show promise for preserving heart function and reducing fibrosis.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Single-cell Genomics
Background:
- Pathological cardiac hypertrophy precedes heart failure, a leading cause of cardiovascular mortality.
- Current treatments offer limited relief post-heart failure onset.
- Need for cell type- and stage-specific therapeutic strategies is critical.
Purpose of the Study:
- To analyze cell type dynamics and interactions during pressure overload-induced cardiac hypertrophy.
- To identify potential pharmacological targets for intervention.
- To validate findings in human cardiac disease samples.
Main Methods:
- Single-cell RNA sequencing of 11,492 cells from a mouse model of cardiac hypertrophy.
- Identification of major cardiac cell types and subtypes based on molecular signatures.
- In vivo testing of pharmacological interventions targeting identified cellular pathways.
Main Results:
- Detailed characterization of cardiomyocyte, endothelial, fibroblast, and macrophage dynamics during hypertrophy progression.
- Demonstrated stagewise crosstalk between cell types, with specific noncardiomyocyte roles.
- Macrophage activation and subtype switching identified as a key middle-stage event, successfully targeted by Dapagliflozin, TD139, and Arglabin to preserve cardiac function and attenuate fibrosis.
- Identified similar molecular patterns in human hypertrophic cardiomyopathy and heart failure samples.
Conclusions:
- The study elucidates dynamic cell-cell communication in pathological cardiac hypertrophy.
- Provides a basis for developing cell type- and stage-specific interventions for cardiac diseases.
- Highlights the therapeutic potential of targeting macrophage dynamics in heart conditions.
Background:
Pressure overload-induced pathological cardiac hypertrophy is a common predecessor of heart failure, the latter of which remains a major cardiovascular disease with increasing incidence and mortality worldwide. Current therapeutics typically involve partially relieving the heart's workload after the onset of heart failure. Thus, more pathogenesis-, stage-, and cell type-specific treatment strategies require refined dissection of the entire progression at the cellular and molecular levels.
Methods:
By analyzing the transcriptomes of 11,492 single cells and identifying major cell types, including both cardiomyocytes and noncardiomyocytes, on the basis of their molecular signatures, at different stages during the progression of pressure overload-induced cardiac hypertrophy in a mouse model, we characterized the spatiotemporal interplay among cell types, and tested potential pharmacological treatment strategies to retard its progression in vivo.
Results:
We illustrated the dynamics of all major cardiac cell types, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, as well as those of their respective subtypes, during the progression of disease. Cellular crosstalk analysis revealed stagewise utilization of specific noncardiomyocytes during the deterioration of heart function. Specifically, macrophage activation and subtype switching, a key event at middle-stage of cardiac hypertrophy, was successfully targeted by Dapagliflozin, a sodium glucose cotransporter 2 inhibitor, in clinical trials for patients with heart failure, as well as TD139 and Arglabin, two anti-inflammatory agents new to cardiac diseases, to preserve cardiac function and attenuate fibrosis. Similar molecular patterns of hypertrophy were also observed in human patient samples of hypertrophic cardiomyopathy and heart failure.
Conclusions:
Together, our study not only illustrated dynamically changing cell type crosstalk during pathological cardiac hypertrophy but also shed light on strategies for cell type- and stage-specific intervention in cardiac diseases.
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