Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy
Mark Chaffin1, Irinna Papangeli2, Bridget Simonson1
1Precision Cardiology Laboratory and the Cardiovascular Disease Initiative, The Broad Institute, Cambridge, MA, USA.
Insights
Researchers discovered unique activated fibroblasts in heart failure using single-nucleus RNA sequencing. This finding offers new therapeutic targets and biomarkers for heart failure, improving understanding of cardiac disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genomics
Background:
- Heart failure is a complex condition with impaired cardiac function.
- Previous studies focused on major cell types, potentially missing molecular changes in rarer cells.
- Understanding the full molecular landscape of heart failure is crucial for developing effective treatments.
Purpose of the Study:
- To comprehensively map molecular alterations in failing hearts at single-cell resolution.
- To identify novel cell populations and molecular pathways involved in heart failure pathogenesis.
- To discover potential therapeutic targets and biomarkers for heart failure.
Main Methods:
- Single-nucleus RNA sequencing of nearly 600,000 nuclei from human left ventricle samples.
- Analysis of samples from patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, and non-failing controls.
- CRISPR-knockout screen in primary human cardiac fibroblasts to investigate fibrotic cell-state transitions.
Main Results:
- Identified extensive molecular alterations in failing hearts at single-cell resolution.
- Observed convergent transcriptional profiles in dilated and hypertrophic cardiomyopathy hearts.
- Discovered a unique population of activated fibroblasts in cardiomyopathy hearts, largely absent in non-failing hearts.
- CRISPR screening revealed key genes regulating fibroblast to myofibroblast transition.
Conclusions:
- Single-nucleus RNA sequencing provides unprecedented insight into the transcriptional diversity of the human heart in health and disease.
- Activated fibroblasts represent a potential therapeutic target in heart failure.
- These findings offer new biomarkers and therapeutic strategies for heart failure management.
Abstract:
Heart failure encompasses a heterogeneous set of clinical features that converge on impaired cardiac contractile function1,2 and presents a growing public health concern. Previous work has highlighted changes in both transcription and protein expression in failing hearts3,4, but may overlook molecular changes in less prevalent cell types. Here we identify extensive molecular alterations in failing hearts at single-cell resolution by performing single-nucleus RNA sequencing of nearly 600,000 nuclei in left ventricle samples from 11 hearts with dilated cardiomyopathy and 15 hearts with hypertrophic cardiomyopathy as well as 16 non-failing hearts. The transcriptional profiles of dilated or hypertrophic cardiomyopathy hearts broadly converged at the tissue and cell-type level. Further, a subset of hearts from patients with cardiomyopathy harbour a unique population of activated fibroblasts that is almost entirely absent from non-failing samples. We performed a CRISPR-knockout screen in primary human cardiac fibroblasts to evaluate this fibrotic cell state transition; knockout of genes associated with fibroblast transition resulted in a reduction of myofibroblast cell-state transition upon TGFβ1 stimulation for a subset of genes. Our results provide insights into the transcriptional diversity of the human heart in health and disease as well as new potential therapeutic targets and biomarkers for heart failure.
Related Concept Videos
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01:30Cardiomyopathy II: Dilated Cardiomyopathy