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Published on: March 22, 2017
Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy
Jason Laird1, Gayani Perera2, Rebecca Batorsky3
1Research Technology, Tufts University, Medford, MA 02144, USA.
Insights
Spatial transcriptomics reveals key molecular pathways in Hypertrophic Cardiomyopathy (HCM). This study identifies novel therapeutic targets by analyzing gene expression changes in affected heart tissue, offering hope for new treatments for this inherited disorder.
Area of Science:
- Cardiovascular Biology
- Genomics
- Molecular Pathology
Background:
- Hypertrophic Cardiomyopathy (HCM) is a common inherited heart condition leading to heart failure and sudden cardiac death.
- Histological hallmarks include myocyte disarray, hypertrophy, and fibrosis, with limited targeted therapies available.
- Identifying spatially restricted molecular alterations is crucial for discovering novel therapeutic targets.
Purpose of the Study:
- To perform spatial transcriptomic analysis on HCM tissue to identify focal transcriptional pathway alterations.
- To compare gene expression in areas of myocyte disarray versus normal tissue within HCM samples.
- To uncover novel, disease-modifying therapeutic targets for Hypertrophic Cardiomyopathy.
Main Methods:
- Spatial transcriptomic analysis using the GeoMx (nanoString) platform on surgical myectomy tissue from HCM patients and control hearts.
- Interrogation of 1800 transcripts using the Human Cancer Transcriptome Atlas.
- Differential gene expression, functional enrichment, ligand-receptor, and deconvolution analyses using matched single nuclei RNA-sequencing (snRNA-seq) data.
Main Results:
- Significant gene expression changes were observed between HCM and control tissues, enriched for interferon production and mitochondrial energetics.
- Within HCM tissue, severe disarray areas showed enrichment for mitochondrial energetics and extracellular matrix genes.
- Differential cell composition, particularly fibroblasts and vascular cells, was identified in severe disarray areas.
Conclusions:
- Spatial transcriptomics effectively identifies focal molecular changes in Hypertrophic Cardiomyopathy.
- Key pathways implicated include interferon signaling, mitochondrial energetics, and extracellular matrix remodeling.
- The study reveals novel potential therapeutic targets and highlights differences in cell composition associated with disease severity in HCM.
Abstract:
Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder that can lead to heart failure and sudden cardiac death, characterized at the histological level by focal areas of myocyte disarray, hypertrophy and fibrosis, and only a few disease-targeted therapies exist. To identify the focal and spatially restricted alterations in the transcriptional pathways and reveal novel therapeutic targets, we performed a spatial transcriptomic analysis of the areas of focal myocyte disarray compared to areas of normal tissue using a commercially available platform (GeoMx, nanoString). We analyzed surgical myectomy tissue from four patients with HCM and the control interventricular septum tissue from two unused organ donor hearts that were free of cardiovascular disease. Histological sections were reviewed by an expert pathologist, and 72 focal areas with varying degrees of myocyte disarray (normal, mild, moderate, severe) were chosen for analysis. Areas of interest were interrogated with the Human Cancer Transcriptome Atlas designed to profile 1800 transcripts. Differential expression analysis revealed significant changes in gene expression between HCM and the control tissue, and functional enrichment analysis indicated that these genes were primarily involved in interferon production and mitochondrial energetics. Within the HCM tissue, differentially expressed genes between areas of normal and severe disarray were enriched for genes related to mitochondrial energetics and the extracellular matrix in severe disarray. An analysis of the gene expression of the ligand-receptor pair revealed that the HCM tissue exhibited downregulation of platelet-derived growth factor (PDGF), NOTCH, junctional adhesion molecule, and CD46 signaling while showing upregulation of fibronectin, CD99, cadherin, and amyloid precursor protein signaling. A deconvolution analysis utilizing the matched single nuclei RNA-sequencing (snRNA-seq) data to determine cell type composition in areas of interest revealed significant differences in fibroblast and vascular cell composition in areas of severe disarray when compared to normal areas in HCM samples. Cell composition in the normal areas of the control tissue was also divergent from the normal areas in HCM samples, which was consistent with the differential expression results. Overall, our data identify novel and potential disease-modifying targets for therapy in HCM.
