Spatial transcriptomics for CD36/FABP5/PPARδ signaling axis defines spontaneously proliferating cardiomyocytes in neonatal stages
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE290093 | GEO | 2026/02/20
REPOSITORIES: GEO
Similar Datasets
Project description:Spontaneously cycling cardiomyocytes (CMs) represent a rare and unique population in the neonatal heart with the potential to drive cardiac regeneration in adulthood. While previous studies have observed their existence, the mechanisms regulating their cell cycle activity remain poorly understood. Here, we aim to identify the signaling axis that defines the spontaneously proliferating CMs in the neonatal stage.
2026-02-19 | GSE290000 | GEO
Project description:CD36/FABP5/PPARδ signaling axis defines spontaneously proliferating cardiomyocytes in neonatal stages
| PRJNA1225722 | ENA
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:Mitochondria play a crucial role in the differentiation and maturation of human cardiomyocytes (CMs). To identify mitochondrial pathways and regulators that are involved in cardiac differentiation and maturation, we examined human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Proteomic analysis was performed on enriched mitochondrial protein extracts isolated from hiPSC-CMs differentiated from dermal fibroblasts (dFCM) and cardiac fibroblasts (cFCM), at different days of differentiation (between 12 and 115 days), and also from adult and neonatal mouse hearts for comparison. Mitochondrial proteins with a ≥2-fold change between differentiation time points in dFCMs and cFCMs, and between adult versus neonatal mouse hearts, were subjected to Ingenuity Pathway Analysis (IPA), and some upregulated proteins were validated by immunoblotting. The highest significant upregulation was in metabolic pathways for fatty acid oxidation (FAO), the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS) and branched chain amino acid (BCAA) catabolism. The top upstream regulators predicted by IPA were- peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-a), the insulin receptor and the retinoblastoma protein (Rb) transcriptional repressor. In addition, IPA and immunoblotting showed substantial upregulation of the mitochondrial LonP1 protease, which regulates mitochondrial proteostasis, energetics and metabolism. Using this proteomics approach, we have identified key metabolic and intracellular signaling pathways that are up- and down- regulated during the biogenesis of mitochondria in differentiating and maturing cardiac myocytes.
2022-05-19 | PXD014317 | Pride
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:Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold tremendous promise for in vitro modeling 2 to assess native myocardial function and disease mechanisms as well as testing drug safety and efficacy. However, 3 current iPSC-CMs are functionally immature, resembling in vivo CMs of fetal or neonatal developmental states. The 4 use of targeted culture media and organoid formats have been identified as potential high-yield contributors to 5 improve CM maturation. This study presents a novel iPSC-CM maturation medium formulation, designed using a 6 differential evolutionary approach targeting metabolic functionality for iterative optimization. Relative to gold-7 standard reference formulations, our medium significantly matured morphology, Ca2+ handling, electrophysiology, 8 and metabolism, which was further validated by multi-omic screening, for cells in either pure or co-cultured 9 microtissue formats. Together, these findings not only provide a reliable workflow for highly functional iPSC-CMs 10 for downstream use, but also demonstrate the power of high-dimensional optimization processes in evoking 11 advanced biological function in vitro.
2026-02-16 | PXD036639 | Pride
Project description:Human induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used to identify potential factors capable of inducing endogenous cardiomyocyte proliferation to regenerate the injured heart. L-type calcium channel blockers have previously been identified as a class of factors capable of inducing matured hiPSC-CMs to proliferate. However, the mechanism by which L-type calcium channel blockers promote hiPSC-CM proliferation remains unclear. Here we provide evidence that matured hiPSC-CMs possess plasticity to undergo dematuration in response to certain pharmacological compounds. Consistent with primary cardiomyocyte maturation during perinatal development, we found that centrosome disassembly occurs in hiPSC-CMs during plate-based, temporal, maturation. A small molecule screen identified Nitrendipine, an L-type calcium channel blocker, and 1-NA-PP1, a Src kinase inhibitor, as factors capable of inducing centrosome reassembly in a subpopulation of hiPSC-CMs. Furthermore, centrosome-positive hiPSC-CMs were more likely to exhibit cell cycle activity than centrosome-negative hiPSC-CMs. In contrast, neither Nitrendipine or 1-NA-PP1 induced centrosome reassembly, or cell cycle activity, in neonatal rat ventricular myocytes (NRVMs). Differential bulk transcriptome analysis indicated that matured hiPSC-CMs, but not NRVMs, treated with Nitrendipine or 1-NA-PP1 undergo dematuration. ScRNA transcriptome analysis supported that matured hiPSC-CMs treated with either Nitrendipine or 1-NA-PP1 undergo dematuration. Collectively, our results indicate that matured hiPSC-CMs, but not primary NRVMs, possess plasticity to undergo dematuration in response to certain pharmacological compounds such as L-type calcium channel blockers and Src-kinase inhibitors. This study shows that once mature, hiPSC-CMs may not maintain their maturity under experimental conditions and thus may have implications for experimental systems where the state of hiPSC-CM maturation is relevant.
2025-04-23 | GSE263350 | GEO
Project description:The restricted regenerative potential of adult hearts poses a significant barrier to effective repair following injury. In contrast to numerous vertebrates, mammalian hearts exhibit only transient neonatal renewal capacity during the initial days of life. Beyond cardiomyocytes, understanding the diverse compositions of non-cardiomyocytes (non-CMs) is imperative for maintaining heart microenvironment homeostasis during neonatal heart regeneration. Here, we conducted single-cell ATAC sequencing (scATAC-seq) on neonatal hearts at varying time points post-apical resection to profile the epigenetic landscape. Intriguingly, fibroblasts and endothelial cells, as the most abundant populations in the heart, exhibited the most dynamic chromatin remodeling as the heart loses its regenerative potential. Our application of scATAC-seq unveiled key regulatory elements such as Cebpd in fibroblast activation and proliferation, while highlighting the essential role of AP-1 in endothelial cell angiogenesis, migration, and proliferation. Additionally, we uncovered active engagement of regulatory elements identified by non-CMs in regulating the behavior of cardiomyocytes, inhibition of which impaired cardiac function post-injury. Collectively, our study delineates the cellular identity of non-CMs at the epigenome level using single-cell approaches, offering insights into cell-type-targeted interventions for heart regeneration.
2025-11-07 | GSE269164 | GEO