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Published on: March 22, 2017
Spatial transcriptional landscape of human heart failure
Sang Eun Lee1,2, Jeong Ho Joo3, Hee Sang Hwang4
1Department of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Insights
This study reveals cell-specific gene expression changes in heart failure (HF) cardiomyopathies. Key genes in cardiomyocytes and endothelial cells offer new insights into HF progression and potential therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Molecular Pathology
- Genomics
Background:
- Heart failure (HF) presents a significant clinical challenge with complex pathophysiology.
- Molecular changes in specific cell types during HF progression are not well understood.
Purpose of the Study:
- To investigate cell-type- and histology-specific gene expression profiles in various cardiomyopathies.
- To identify molecular alterations associated with HF pathogenesis.
Main Methods:
- Analysis of 90 tissue cores from 44 participants with diverse cardiomyopathies and controls using the GeoMx Whole Human Transcriptome Atlas.
- Integration of cell type, clinical, and histological data for gene expression analysis.
- Validation using multiplex immunohistochemistry and prior single-cell/nucleus RNA sequencing (sc/snRNA-seq) data.
Main Results:
- The GeoMx platform accurately compartmentalized cell types, particularly cardiomyocytes.
- Differential gene expression linked to degeneration (e.g., UCHL1 in cardiomyocytes) and fibrosis (e.g., CCL14, ACKR1, PLVAP in endothelial cells).
- A pro-inflammatory endothelial cell subtype (PLVAP+, ACKR1+, CCL14+) was identified in HF-associated fibrosis. Downregulation of ribosomal proteins in cardiomyocytes correlated with myocyte disarray. Novel contributors CRIP3, PFKFB2, and TAX1BP3 were identified.
Conclusions:
- Cell-enriched and histology-specific transcriptome mapping is crucial for understanding failing heart pathophysiology.
- The study provides molecular insights into HF progression.
- Identified molecular signatures may serve as potential therapeutic targets for HF interventions.
Background And Aims:
Heart failure (HF) remains a significant clinical challenge due to its diverse aetiologies and complex pathophysiology. The molecular alterations specific to distinct cell types and histological patterns during HF progression are still poorly characterized. This study aimed to explore cell-type- and histology-specific gene expression profiles in cardiomyopathies.
Methods:
Ninety tissue cores from 44 participants, encompassing various forms of cardiomyopathy and control samples with diverse histological features, were analysed using the GeoMx Whole Human Transcriptome Atlas. Data on cell types, clinical information, and histological features were integrated to examine gene expression profiles in cardiomyopathy.
Results:
The study characterized the cellular composition of ventricular myocardium and validated the GeoMx platform's efficiency in compartmentalizing specific cell types, demonstrating high accuracy for cardiomyocytes but limitations for endothelial cells and fibroblasts. Differentially expressed genes, including UCHL1 from cardiomyocytes, were associated with degeneration, while CCL14, ACKR1, and PLVAP from endothelial cells were linked to fibrosis. Multiplex immunohistochemistry and integrative analysis of prior sc/snRNA-seq data identified a PLVAP, ACKR1, and CCL14-positive pro-inflammatory endothelial cell subtype linked to fibrosis in HF. Downregulation of ribosomal proteins in cardiomyocytes was associated with myocyte disarray in hypertrophic cardiomyopathy. Additionally, pronounced inflammatory responses were observed in end-stage HF. Combined histological and clinical analysis identified CRIP3, PFKFB2, and TAX1BP3 as novel contributors to HF pathogenesis.
Conclusions:
These findings highlight the critical role of cell-enriched and histology-specific transcriptome mapping in understanding the complex pathophysiological landscape of failing hearts, offering molecular insights and potential therapeutic targets for future interventions.
