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Exploring the role of Hic1 : an essential transcription factor in mouse heart development Kahlani, Mohammadjavad
Abstract
Heart development is a highly regulated process governed by complex gene expression patterns, with mesenchymal cells playing a critical role in shaping the heart's structure. Hypermethylated in cancer 1 (Hic1), a transcription factor, is essential for maintaining the quiescent state of mesenchymal progenitor cells in the adult heart and is expressed during the epicardial-to-mesenchymal transition within the atrioventricular canal during embryogenesis. However, its broader role in cardiac development remains largely unexplored. To address this gap, this study employed single-cell transcriptomics to analyze Hic1 knock-out (KO) and wild-type (WT) mouse hearts at E16.5. Unexpectedly, Hic1 expression was detected not only in epicardial and a portion of mesenchymal cells but also in endocardial and endothelial cells of wild-type hearts. A comparative analysis of mesenchymal cell heterogeneity between KO and WT hearts revealed significant alterations in mesenchymal cell populations in Hic1-KO hearts. Notably, pericytes, which are vital for angiogenesis and stabilizing blood vessels, were absent in the KO hearts. Given that pericytes typically arise from epicardial cells through epithelial-to-mesenchymal transition, their absence in Hic1-KO hearts suggests that Hic1 is crucial for their differentiation. Additionally, an increased presence of activated fibroblasts was observed in the KO hearts. These fibroblasts exhibited gene expression profiles typical of a myofibroblast state, which is associated with tissue repair and characterized by contractile properties and involvement in extracellular matrix (ECM) remodeling. Genes such as Pdgfa, Acta2, Tagln, and Sdc4, commonly linked to myofibroblast activation, were upregulated, indicating a shift toward a more activated phenotype in the absence of Hic1. While these fibroblasts exhibited an enhanced expression of migratory genes, their expression profile did not fully align with a typical myofibroblast signature, as hallmark genes like collagen type I and TGF-β signaling were not upregulated. Instead, these cells expressed collagen type IV, further indicating a distinct yet activated phenotype. Additionally, endocardial cells in the KO hearts showed increased interactions and upregulation of genes promoting angiogenesis, possibly due to improper vascularization. These findings underscore the role of Hic1 in regulating mesenchymal cell heterogeneity and highlight its importance in maintaining normal heart development through the control of fate determinations and ECM remodeling.
Item Metadata
Title |
Exploring the role of Hic1 : an essential transcription factor in mouse heart development
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Creator | |
Supervisor | |
Publisher |
University of British Columbia
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Date Issued |
2024
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Description |
Heart development is a highly regulated process governed by complex gene expression patterns, with mesenchymal cells playing a critical role in shaping the heart's structure. Hypermethylated in cancer 1 (Hic1), a transcription factor, is essential for maintaining the quiescent state of mesenchymal progenitor cells in the adult heart and is expressed during the epicardial-to-mesenchymal transition within the atrioventricular canal during embryogenesis. However, its broader role in cardiac development remains largely unexplored. To address this gap, this study employed single-cell transcriptomics to analyze Hic1 knock-out (KO) and wild-type (WT) mouse hearts at E16.5. Unexpectedly, Hic1 expression was detected not only in epicardial and a portion of mesenchymal cells but also in endocardial and endothelial cells of wild-type hearts. A comparative analysis of mesenchymal cell heterogeneity between KO and WT hearts revealed significant alterations in mesenchymal cell populations in Hic1-KO hearts. Notably, pericytes, which are vital for angiogenesis and stabilizing blood vessels, were absent in the KO hearts. Given that pericytes typically arise from epicardial cells through epithelial-to-mesenchymal transition, their absence in Hic1-KO hearts suggests that Hic1 is crucial for their differentiation. Additionally, an increased presence of activated fibroblasts was observed in the KO hearts. These fibroblasts exhibited gene expression profiles typical of a myofibroblast state, which is associated with tissue repair and characterized by contractile properties and involvement in extracellular matrix (ECM) remodeling. Genes such as Pdgfa, Acta2, Tagln, and Sdc4, commonly linked to myofibroblast activation, were upregulated, indicating a shift toward a more activated phenotype in the absence of Hic1. While these fibroblasts exhibited an enhanced expression of migratory genes, their expression profile did not fully align with a typical myofibroblast signature, as hallmark genes like collagen type I and TGF-β signaling were not upregulated. Instead, these cells expressed collagen type IV, further indicating a distinct yet activated phenotype. Additionally, endocardial cells in the KO hearts showed increased interactions and upregulation of genes promoting angiogenesis, possibly due to improper vascularization. These findings underscore the role of Hic1 in regulating mesenchymal cell heterogeneity and highlight its importance in maintaining normal heart development through the control of fate determinations and ECM remodeling.
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Genre | |
Type | |
Language |
eng
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Date Available |
2024-11-25
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0447329
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2025-05
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International