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An injury-associated transient progenitor state in the epicardium mediates heart regeneration

ABSTRACT: An injury-associated transient progenitor state in the epicardium mediates heart regeneration

PROVIDER: PRJNA837476 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19176074.fastq.gz	Fastqsanger.gz
	SRR19176075.fastq.gz	Fastqsanger.gz
	SRR19176076.fastq.gz	Fastqsanger.gz
	SRR19176077.fastq.gz	Fastqsanger.gz
	SRR19176078.fastq.gz	Fastqsanger.gz

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An injury-associated transient progenitor state in the epicardium mediates heart regeneration

Project description:Adult zebrafish regenerate heart muscle after severe cardiac damage without significant scarring. The epicardium, a mesothelial cell sheet covering the vetebrate heart, is activated by injury and supports muscle regeneration through paracrine effects and as a source of multipotent cells. The understudied cellular heterogeneity of the adult epicardium during heart regeneration has constrained the effort in mobilizing the epicardium for heart repair. To dissect epicardial cell states and the underlying mechanisms that lead to successful heart regeneration in zebrafish, we performed single-cell RNA-sequencing of isolated epicardial cells from the regenerating adult heart and revealed their dynamic cellular heterogeneity. We defined the epithelial and mesenchymal layers of the epicardium and identified a transiently activated epicardial progenitor cell (aEPC) subpopulation that expresses aldh1a2, ptx3a, col12a1b and marcksb. Upon heart amputation injury, aEPCs emerge from the existing epicardial cells, migrate to enclose the wound, and disappear as regeneration progresses. Genetic lineage tracing combined with modified RNA labelling confirmed an epithelial-mesenchymal transition (EMT) process of aEPCs and their differentiations to pdgfrb+ mural cells and pdgfra+hapln1a+ mesenchymal fibroblast-like cells that support heart regeneration. Genetic ablation of aEPCs blocked wound closure of the injured ventricle, suppressed cardiomyocyte proliferation, and disrupted heart regeneration. Our findings define a transient progenitor state of the adult epicardium that is an indispensable driver of zebrafish heart regeneration and identified ptx3a as a regeneration-specific non-ontogenetic regulator of the epicardium.

2022-11-22 | GSE202836 | GEO

Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration.

Project description:The epicardium, a mesothelial cell tissue that encompasses vertebrate hearts, supports heart regeneration after injury through paracrine effects and as a source of multipotent progenitors. However, the progenitor state in the adult epicardium has yet to be defined. Through single-cell RNA-sequencing of isolated epicardial cells from uninjured and regenerating adult zebrafish hearts, we define the epithelial and mesenchymal subsets of the epicardium. We further identify a transiently activated epicardial progenitor cell (aEPC) subpopulation marked by ptx3a and col12a1b expression. Upon cardiac injury, aEPCs emerge from the epithelial epicardium, migrate to enclose the wound, undergo epithelial-mesenchymal transition (EMT), and differentiate into mural cells and pdgfra+hapln1a+ mesenchymal epicardial cells. These EMT and differentiation processes are regulated by the Tgfβ pathway. Conditional ablation of aEPCs blocks heart regeneration through reduced nrg1 expression and mesenchymal cell number. Our findings identify a transient progenitor population of the adult epicardium that is indispensable for heart regeneration and highlight it as a potential target for enhancing cardiac repair.

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Transient Ddx61-enriched condensates refine heart regeneration programs

Project description:Transient Ddx61-enriched condensates refine heart regeneration programs

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Transient Ddx61-enriched condensates refine heart regeneration programs

Project description:Gene regulatory mechanisms that underlie tissue regeneration have been largely studied at the level of transcription. Here, proximity labeling methods identified enhanced presence of Processing body (P-body) marker, Ddx61, in zebrafish heart muscle cells induced to divide by injury or mitogenic stimulation. We found that Ddx61-containing condensates emerge and develop complex, transient structures in cardiomyocytes during cardiogenic settings in adult zebrafish, developing mice, and human stem cell-derived myocardium. Mutations in zebrafish ddx61 disrupted cardiomyocyte cycling and differentiation after cardiac injury or mitogen presence, and DDX61 knockdown in human cardiomyocytes inhibited similar parameters under maturation conditions in vitro. RNA affinity and proteomic profiling implicated mRNAs preferentially associating with Ddx61 during regeneration, and induced transgenic expression of one of these mRNAs, encoding the BMP signaling inhibitor, Chordin, disrupted indicators of heart regeneration after cardiac injury. Our experiments provide evidence that mRNA sorting by specialized context-dependent condensates can modulate gene expression and impact tissue regenerative capacity.

2025-08-26 | GSE246577 | GEO

Comparing a timecourse of hESC-epicardium differentiation with single-cell adult and foetal human epicardium as part of the study: A single-cell comparison of adult and foetal human epicardium defines the age-associated changes in epicardial activity

Project description:This study is associated with the GEO accession GSE216019. Abstract from article: Re-activating quiescent adult epicardium represents a potential therapeutic approach for human cardiac regeneration. However, the exact molecular differences between inactive adult and active foetal epicardium are not known. Here, we combined foetal and adult human hearts for the first time using single-cell and single-nuclei RNA sequencing, and compared epicardial cells from both stages. We found a migratory fibroblast-like epicardial population only in the foetal heart and foetal epicardium expressed angiogenic gene programs, while the adult epicardium was solely mesothelial and immune-responsive. Furthermore, we predicted that adult hearts may still receive foetal epicardial paracrine communication, including WNT-signalling with endocardium, reinforcing the validity of regenerative strategies that administer or reactivate epicardial cells in situ. Finally, we explained graft efficacy of our human embryonic stem-cell derived epicardium model, by noting its similarity to human foetal epicardium. Overall, our study defines epicardial programs of regenerative angiogenesis absent in adult hearts, contextualises animal studies, and defines epicardial endpoints required for effective human heart regeneration.

2022-10-31 | GSE216177 | GEO

Generation of mature epicardium derived from human-induced pluripotent stem cells via inhibition of mTOR signaling

Project description:Reactivating the human epicardium post-cardiac injury holds promise for cardiac tissue regeneration. Despite successful differentiation protocols yielding pure, self-renewing epicardial cells from induced pluripotent stem cells (iPSCs), these cells maintain an embryonic, proliferative state, impeding adult epicardial reactivation investigation. We introduce an optimized method that employs mammalian target of rapamycin (mTOR) signaling inhibition in embryonic epicardium, inducing a quiescent state that enhances multi-step epicardial maturation. This yields functionally mature epicardium, valuable for modeling adult epicardial reactivation. Furthermore, we assess cardiac organoids with cardiomyocytes and mature epicardium, probing molecular mechanisms governing epicardial quiescence during cardiac maturation. Our results highlight iPSC-derived mature epicardium's potential in investigating adult epicardial reactivation, pivotal for effective cardiac regeneration. Additionally, the cardiac organoid model offers insight into intricate cardiomyocyte-epicardium interactions in cardiac development and regeneration.

2025-06-30 | GSE252590 | GEO

scRNA-seq of E15.5 epicardium and epicardium-derived cells

Project description:scRNA-seq of E15.5 epicardium and epicardium-derived cells

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Transient restriction of intercellular communication is required for root regeneration

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2023-11-24 | GSE248204 | GEO

A single-cell comparison of adult and foetal human epicardium defines the age-associated changes in epicardial activity

Project description:Re-activating quiescent adult epicardium represents a potential therapeutic approach for human cardiac regeneration. However, the exact molecular differences between inactive adult and active foetal epicardium are not known. Here, we combined foetal and adult human hearts for the first time using single-cell and single-nuclei RNA sequencing, and compared epicardial cells from both stages. We found a migratory fibroblast-like epicardial population only in the foetal heart and foetal epicardium expressed angiogenic gene programs, while the adult epicardium was solely mesothelial and immune-responsive. Furthermore, we predicted that adult hearts may still receive foetal epicardial paracrine communication, including WNT-signalling with endocardium, reinforcing the validity of regenerative strategies that administer or reactivate epicardial cells in situ. Finally, we explained graft efficacy of our human embryonic stem-cell derived epicardium model, by noting its similarity to human foetal epicardium. Overall, our study defines epicardial programs of regenerative angiogenesis absent in adult hearts, contextualises animal studies, and defines epicardial states required for effective human heart regeneration.

2022-10-31 | GSE216019 | GEO

Positional information modulates transient regeneration-activated cell states during vertebrate appendage regeneration.

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