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Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy

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 s...

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Autores principales: Laird, Jason, Perera, Gayani, Batorsky, Rebecca, Wang, Hongjie, Arkun, Knarik, Chin, Michael T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454036/
https://www.ncbi.nlm.nih.gov/pubmed/37628806
http://dx.doi.org/10.3390/ijms241612625
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author Laird, Jason
Perera, Gayani
Batorsky, Rebecca
Wang, Hongjie
Arkun, Knarik
Chin, Michael T.
author_facet Laird, Jason
Perera, Gayani
Batorsky, Rebecca
Wang, Hongjie
Arkun, Knarik
Chin, Michael T.
author_sort Laird, Jason
collection PubMed
description 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.
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spelling pubmed-104540362023-08-26 Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy Laird, Jason Perera, Gayani Batorsky, Rebecca Wang, Hongjie Arkun, Knarik Chin, Michael T. Int J Mol Sci Article 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. MDPI 2023-08-10 /pmc/articles/PMC10454036/ /pubmed/37628806 http://dx.doi.org/10.3390/ijms241612625 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Laird, Jason
Perera, Gayani
Batorsky, Rebecca
Wang, Hongjie
Arkun, Knarik
Chin, Michael T.
Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy
title Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy
title_full Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy
title_fullStr Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy
title_full_unstemmed Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy
title_short Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy
title_sort spatial transcriptomic analysis of focal and normal areas of myocyte disarray in human hypertrophic cardiomyopathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454036/
https://www.ncbi.nlm.nih.gov/pubmed/37628806
http://dx.doi.org/10.3390/ijms241612625
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