What is the clinical evidence from this study?

Study design: Other. Population: Myocardial injury and heart regeneration. Intervention: Cebpd knockdown (shRNA) and AP-1 inhibition (T-5224) vs. Wild-type, scrambled shRNA, and vehicle controls. Primary outcome: Chromatin accessibility dynamics and cardiac tissue regeneration.

What does this research mean for the field?

CEBPD and AP-1 transcription factors orchestrate beneficial fibroblast activation and angiogenesis crucial for neonatal heart regeneration through dynamic chromatin remodeling in cardiac non-myocytes. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The study aims to explore the epigenetic landscape of cardiac non-myocytes during regeneration.

March 7, 2026Open Access

Single-cell chromatin accessibility landscape of cardiac non-myocytes identifies tissue repair program during heart regeneration

Key Result

Single-cell ATAC sequencing of 57,899 cardiac cells revealed that CEBPD and AP-1 transcription factors orchestrate beneficial fibroblast activation and angiogenesis crucial for neonatal heart regeneration.

Key Points

The study aims to explore the epigenetic landscape of cardiac non-myocytes during regeneration.
Performed single-cell ATAC sequencing on neonatal hearts at different recovery stages after injury.
Analyzed chromatin dynamics in fibroblasts and endothelial cells post-apical resection.
Identified dynamic chromatin remodeling in fibroblasts and endothelial cells following cardiac injury.
Highlighted CEBPD and AP-1 as key factors regulating fibroblast activation and angiogenesis.

Structured PICO

Population

Neonatal wild-type (WT) and SphK2-/- mice (C57BL/6J), and Human Umbilical Vein Endothelial Cells (HUVECs).

Intervention

Apical resection surgery evaluated at 3, 7, and 14 days post-surgery with single-cell ATAC sequencing; in vitro treatment with AP-1 inhibitor T-5224 (15 µM).

Comparator

Uninjured WT controls at corresponding timepoints and non-regenerative SphK2-/- mice.

Outcome

Chromatin accessibility landscape and epigenetic remodeling of cardiac non-cardiomyocytes.surrogate

CEBPD and AP-1 transcription factors drive essential epigenetic remodeling in cardiac fibroblasts and endothelial cells during neonatal heart regeneration, identifying potential therapeutic targets for cardiac repair.

Limitations

Motif-enrichment analyses across all endothelial cell subtypes were constrained by the transient nature of the EC3 population.

Abstract

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 conduct single-cell ATAC sequencing 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, exhibit the most dynamic chromatin remodeling upon injury. Furthermore, we reveal CEBPD and AP-1 family transcriptional factors as pivotal trans-regulators orchestrating these alterations, governing beneficial fibroblast activation and endothelial cell angiogenesis crucial for cardiac regeneration, respectively. 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.

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