Identifying transcription factors distinguishing regenerating cardiomyocytes in the zebrafish heart using single cell transcriptomics
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE280871 | GEO | 2026/09/01
REPOSITORIES: GEO
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Project description:The regenerative capacity of the adult mammalian heart is constrained by the post-mitotic nature of cardiomyocytes (CMs). Conversely, neonatal mouse hearts exhibit a regenerative window within the first week of life. Here, we demonstrate that an injury-induced Clusterin-positive (Clu+) CM population reprograms macrophages, facilitating heart regeneration during this timeframe. Clu+ CMs are selectively induced in the border zone of regenerative hearts across multiple species, contrasting with their absence in non-regenerative hearts. Genetic ablation of Clu+ CMs or Clu impedes neonatal heart regeneration, while transplantation of engineered human organoids enriched in Clu+ CMs or Clu overexpression promotes myocardial regeneration in adult mice. Mechanistically, Clu+ CMs secrete CLU, binding to TLR4 in macrophages, directing them toward an immune-suppressive neonatal-like phenotype through Cpt1a-mediated metabolic reprogramming, inducing BMP2 and promoting CM proliferation. Our findings unveil a novel cellular source for mammalian heart regeneration and highlight the fundamental roles of cardio-immune interaction in cardiac repair.
2025-11-24 | GSE253859 | GEO
Project description:The regenerative capacity of the adult mammalian heart is constrained by the post-mitotic nature of cardiomyocytes (CMs). Conversely, neonatal mouse hearts exhibit a regenerative window within the first week of life. Here, we demonstrate that an injury-induced Clusterin-positive (Clu+) CM population reprograms macrophages, facilitating heart regeneration during this timeframe. Clu+ CMs are selectively induced in the border zone of regenerative hearts across multiple species, contrasting with their absence in non-regenerative hearts. Genetic ablation of Clu+ CMs or Clu impedes neonatal heart regeneration, while transplantation of engineered human organoids enriched in Clu+ CMs or Clu overexpression promotes myocardial regeneration in adult mice. Mechanistically, Clu+ CMs secrete CLU, binding to TLR4 in macrophages, directing them toward an immune-suppressive neonatal-like phenotype through Cpt1a-mediated metabolic reprogramming, inducing BMP2 and promoting CM proliferation. Our findings unveil a novel cellular source for mammalian heart regeneration and highlight the fundamental roles of cardio-immune interaction in cardiac repair.
2025-11-24 | GSE254056 | GEO
Project description:The regenerative capacity of the adult mammalian heart is constrained by the post-mitotic nature of cardiomyocytes (CMs). Conversely, neonatal mouse hearts exhibit a regenerative window within the first week of life. Here, we demonstrate that an injury-induced Clusterin-positive (Clu+) CM population reprograms macrophages, facilitating heart regeneration during this timeframe. Clu+ CMs are selectively induced in the border zone of regenerative hearts across multiple species, contrasting with their absence in non-regenerative hearts. Genetic ablation of Clu+ CMs or Clu impedes neonatal heart regeneration, while transplantation of engineered human organoids enriched in Clu+ CMs or Clu overexpression promotes myocardial regeneration in adult mice. Mechanistically, Clu+ CMs secrete CLU, binding to TLR4 in macrophages, directing them toward an immune-suppressive neonatal-like phenotype through Cpt1a-mediated metabolic reprogramming, inducing BMP2 and promoting CM proliferation. Our findings unveil a novel cellular source for mammalian heart regeneration and highlight the fundamental roles of cardio-immune interaction in cardiac repair.
2025-11-24 | GSE254055 | GEO
Project description:Contrary to adult mammals, zebrafish are able to regenerate their heart after cardiac injury. This regenerative response relies, in part, on the endogenous ability of cardiomyocytes (CMs) to dedifferentiate and proliferate to replenish the lost muscle. However, CM heterogeneity and population dynamics during development and regeneration remain poorly understood. Through comparative transcriptomic analyses of the developing and adult zebrafish heart, we identified tnnc2 and tnni4b.3 expression as markers for CMs at early and late developmental stages, respectively. Using newly developed reporter lines for these genes, we investigated their expression dynamics during development and regeneration, and observed interesting expression patterns. tnnc2 reporter lines label most CMs at embryonic stages, and this labeling declines rapidly during larval stages; in adult hearts expression is only detectable in a subset of CMs. Conversely, expression of a tnni4b.3 reporter is initially visible in outer curvature CMs at larval stages, and it is subsequently present in a vast majority of the CMs in adult hearts. Interestingly, we find that the adult CMs labeled by the embryonic reporter display higher levels of Tg(tp1:EGFP) expression, which indicates active Notch signaling. To further characterize this CM population, we performed transcriptomic analysis and found that it expresses genes encoding components of the Notch signaling pathway as well as markers of immature CMs. Moreover, during heart regeneration, proliferating CMs in the injured area activate the embryonic CM reporter. Overall, our findings provide further evidence of cardiomyocyte heterogeneity in the adult zebrafish heart.
2021-05-03 | GSE157662 | GEO
Project description:Loss of cardiomyocytes (CMs) following injury can lead to myocardial dysfunction, heart failure (HF) and ultimately death. The limited regenerative ability of the adult human heart after injury, however, poses a significant obstacle to restore cardiac function effectively. While mammalian hearts, including those of mice and humans, do have the potential to regenerate, this capacity is restricted to a narrow window during early stages of life. The molecular mechanisms governing the regenerative capacity of mammalian hearts remain incompletely understood. Exploring a comparative transcriptome analysis in regenerative neonatal vs. non-regenerative adult mouse CMs, we identified N-Cadherin, a member of Ca2+-dependent cell adhesion protein cadherin superfamily, as a potential novel regulator of CM proliferation/renewal. The primary objectives of this study were to elucidate the molecular mechanisms through which N-Cadherin regulates cardiomyocyte proliferation and regeneration, and to determine the therapeutic potential to promote CM renewal and restore cardiac function following injury by targeting N-Cadherin. Cardiac N-Cadherin expression exhibits a strong positive correlation with that of cell cycle- and proliferation-related genes. Its expression levels show an age-dependent reduction, with a 75% decrease of N-Cadherin in adult, compared to P1 neonatal, CMs. N-Cadherin expression is upregulated in the neonatal mouse heart in response to apical resection, especially in the peri-injury region, coinciding with increased CM mitotic activities in the neonatal heart. Knocking down N-Cadherin reduced, whereas overexpression of N-Cadherin increased, the proliferation activity of neonatal mouse CMs and human induced pluripotent stem cell-derived CMs. Mechanistically, increased N-Cadherin potentiates CM renewal through direct binding with and stabilization of a pro-mitotic transcription regulator β-Catenin, leading to increased CMs proliferative activity. Deletion of β-Catenin-binding domain on N-Cadherin abrogated its pro-regenerative activity. Importantly, targeted depletion of N-Cadherin in CMs resulted in incomplete cardiac repair/regeneration and excessive fibrotic scar formation in neonatal mouse hearts following injury. Cardiac-specific overexpression of N-Cadherin in adult mouse heart using adeno-associated viral vectors, by contrast, resulted in increased CM proliferation and protected against myocardial infarction-induced adverse remodeling and contractile dysfunction. Adherent junction protein N-cadherin is demonstrated to play a crucial role in maintaining CM renewal potential by post-translational stabilization of β-Catenin. Enhancing N-cadherin expression levels and downstream signaling activities in the heart, therefore, could be a powerful new approach to promote cardiac regeneration and restore myocardial function in adult human heart following injury.
2024-12-08 | GSE253966 | GEO
Project description:The vertebrate heart is composed of heterogeneous cardiomyocyte (CM) populations, however, the roles of distinct CM subpopulations in heart development and repair remain poorly defined. Here, using single-cell RNA sequencing analysis of adult zebrafish heart, we identified a unique CM subpopulation marked by the expression of phlda2, which is associated with anaerobic metabolism and different from mature CMs which are enriched for oxidative phosphorylation genes. We demonstrated that phlda2+ cells constituted a primordial CM compartment localized between compact and trabecular muscles. Genetic ablation of phlda2+ CMs during development severely disrupted heart morphogenesis, leading to defective myocardial trabeculation and compaction, and impaired coronary vascularization. Surprisingly, despite their essential roles in development, the depletion of phlda2+ CMs didn’t impair myocardial restoration and revascularization following ventricular resection. We found that this was probably due to the limited regenerative capacity of the primordial CMs themselves, as they failed to regenerate after either surgical amputation or genetic ablation. Our findings identify primordial CMs as an organizer for heart morphogenesis but not essential for regeneration, revealing a fundamental difference between developmental and regenerative programs in the vertebrate heart.
2026-01-14 | GSE312374 | GEO
Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.
2022-02-15 | PXD011791 | Pride
Project description:It is generally accepted that G2M cell cycle arrest occurs around birth (P3 in mice) as a natural process of cardiomyocyte (CM) terminal differentiation resulting in binucleation/polyploidization that renders the mammalian heart non-regenerative after damage. Mechanisms underlying this postnatal switch in CM proliferation remain unclear. Herein, we developed a novel approach combining fluorescence-activated cell sorting (FACS) with single cell RNA sequencing (scRNA-seq) of fixed CMs and specifically identified transcription factors (TFs) involved in G2M cell cycle completion of mouse CMs.
2023-03-16 | GSE162959 | GEO
Project description:Zebrafish have a high capacity to regenerate their hearts post-injury.Several studies have surveyed transcriptional enhancers to understand how the dynamics of gene expression are controlled during heart regeneration. We have identified a cardiac transcriptional enhancer that is activated at the site of injury called the runx1 enhancer or REN since it regulates the expression of nearby gene runx1. REN is usually active in cardiomyocytes (CMs) and epicardial tissues surrounding the cardiac valves of uninjured zebrafish hearts. However, when REN is activated in regenerating CM and epicardial tissues at the injury site, it is concurrently downregulated around the distal heart valve. Deletion of REN (ΔREN) results in excess Collagen around uninjured zebrafish cardiac valves. This ΔREN Collagen phenotype is rescued with a runx1 deletion (Δrunx1), suggesting that REN and runx1 function in different genetic pathways in uninjured hearts. A different nearby gene that does change expression around valves in ΔREN mutant hearts is adamts1 which encodes a metalloproteinase that degrades Collagen. Taken together, this suggests that in uninjured hearts REN regulates adamts1 independently of runx1. However, during regeneration, CM proliferation at the site of injury is enhanced in both ΔREN and Δrunx1 mutants, suggesting that REN is rewired to runx1 to stimulate its transcription. There are two previous descriptions for how enhancers are activated during regeneration. First, cis-regulatory sequences are reactivated from embryogenesis and second that active adult enhancers are further invigorated during regeneration. Our data point to a third and previously unappreciated mechanism for gene control during zebrafish heart regeneration. We report that an enhancer is repurposed both from one gene and cardiac domain to activate a different nearby gene in regenerating cardiac tissue.
2025-02-03 | GSE279653 | GEO
Project description:Cardiomyocyte (CM) loss after injury results in adverse remodelling and fibrosis, which inevitably lead to heart failure. Neuregulin-ErbB2 and Hippo-Yap signaling pathways are key mediators of CM proliferation and regeneration although the crosstalk between these pathways is unclear. Here, we demonstrate in mice that temporal over-expression (OE) of activated ErbB2 in CMs promotes cardiac regeneration in a heart failure model. Cellularly, OE CMs present an EMT-like regenerative response involving cytoskeletal reprograming, migration, ECM turnover, and displacement. Molecularly, we identified Yap as a critical mediator of ErbB2 signaling. In OE CMs, Yap interacts with nuclear envelope and cytoskeletal components, reflective of the altered mechanic state elicited by ErbB2. Hippo-independent activating phosphorylation on Yap at S352 and S274 were enriched in OE CMs, peaking during metaphase. Viral overexpression of Yap phospho-mutants dampened the proliferative competence of OE CMs. Taken together, we demonstrate a potent ErbB2-mediated Yap mechanosensory signaling involving EMT-like characteristics, resulting in heart regeneration.
2020-08-21 | PXD020731 | Pride