Dissecting Cell-Type Specific Responses through Gene Expression in Heart Injury
Understanding how the heart responds to injury at the level of individual cell types is transforming cardiovascular biology. Historically, studies averaged signals across whole tissue and missed the heterogeneity of responses among cardiomyocytes, fibroblasts, endothelial cells, immune cells and other cardiac-resident populations. Today, single-cell and single-nucleus transcriptomics often integrated with spatial and multi-omic data reveal distinct cell states, dynamic trajectories after injury, and intercellular signalling circuits that drive repair, scarring, or maladaptive remodeling.
When the heart is injured (for example by myocardial infarction, MI), the outcome regeneration versus scar formation and heart failure depends on coordinated responses of multiple cell types and their timing. Bulk RNA measurements blur these contributions. Single-cell (scRNA-seq) and single-nucleus (snRNA-seq) approaches recover cell-type specific transcriptional changes, capture rare subpopulations, and allow reconstruction of dynamic trajectories (activation, proliferation, transdifferentiation) that occur during acute and chronic phases of injury. Combining these data with spatial transcriptomics places cell states back into tissue context crucial for understanding how cellular neighborhoods influence fate decisions.
Core experimental models and technologies (practical overview)
Animal models
Mouse MI (permanent ligation or ischemia reperfusion) remains the main preclinical model; zebrafish and neonatal mice are used to study regenerative programs; larger mammals (pig) model human-like physiology. Cross-species comparisons highlight conserved vs species-specific responses.
scRNA-seq / snRNA-seq
scRNA-seq is excellent for dissociated cells (immune, fibroblasts); snRNA-seq is preferred for fragile cell types such as adult cardiomyocytes and archived/frozen tissues. Many studies now integrate both to maximize coverage.
Multi-omic integration
Single-cell ATAC, protein (CITE-seq), metabolomics and ligand-receptor inference strengthen functional interpretation. Recent multi-omic atlases for the heart are providing reference maps.
Spatial transcriptomics & in situ methods
These map cell states to histology, revealing gradients (e.g., infarct border zone vs remote myocardium) and cell-cell proximity effects.
Major cell-type findings after cardiac injury
Cardiomyocytes stress signatures, limited proliferation
In adult mammals, mature cardiomyocytes show strong stress and fetal-gene reactivation programs after MI (e.g., natriuretic peptides, metabolic reprogramming). Regenerative proliferation is limited in adult hearts, but transcriptomics has identified subpopulations with modest cell-cycle gene induction and stress-adaptive transcriptional states. Cross-species work (e.g., zebrafish vs mouse) highlights genes and pathways associated with regenerative competence that are absent or muted in adult mammalian cardiomyocytes.
Fibroblasts heterogeneous and dynamic drivers of fibrosis
One of the clearest reproducible findings from single-cell atlases is that cardiac fibroblasts are heterogeneous and adopt distinct activation states after injury. Subpopulations include inflammatory fibroblasts (early post-injury), proliferative/myofibroblast states (matrix producing), and specialized scar-forming fibroblasts expressing periostin (Postn+) and other extracellular matrix genes. Integrated single-cell maps have now identified conserved fibroblast activation pathways and candidate regulators that control matrix deposition and scar maturation. Targeting specific fibroblast states (rather than all fibroblasts) is an emerging therapeutic concept.
Endothelial cells and EndMT (endothelial-to-mesenchymal transition)
Endothelial cells respond acutely to ischemia by changing metabolism, upregulating angiogenic programs, and sometimes undergoing partial endothelial-to-mesenchymal transition (EndMT). Recent studies show EndMT is plastic and context-dependent: it can contribute to fibrosis but also supports neovascularization in certain settings. Molecular regulators (transcription factors, noncoding RNAs, signaling axes) that control partial vs full EndMT are a current focus because modulating EndMT could balance angiogenesis and fibrosis.
Immune cells resident vs recruited macrophages and temporal orchestration
Single-cell and multi-omic profiling reveal complex macrophage heterogeneity after cardiac injury. Resident cardiac macrophages often have homeostatic and reparative roles, while recruited monocyte-derived macrophages are more inflammatory and associated with matrix breakdown and infarct expansion when excessive. Subsets such as Trem2+ or CCR2+ macrophages have been linked to reparative or inflammatory programs respectively, and their balance over time critically shapes remodeling. Beyond macrophages, neutrophils, dendritic cells, and lymphocyte subsets also show temporally regulated transcriptional programs that influence outcome.
Other stromal and vascular cell types
Pericytes, smooth muscle cells, lymphatic endothelial cells and nerve-associated cells each adopt injury-specific transcriptional states implicated in angiogenesis, inflammation resolution, lymph drainage, and neural remodeling. Single-cell atlases are now resolving these populations and their localized roles in scar architecture.
Intercellular communication: ligand-receptor signaling and spatial neighborhoods
A major strength of single-cell data is inference of ligand–receptor interactions (e.g., immune→fibroblast, endothelial→cardiomyocyte) and mapping of those signals to tissue microenvironments using spatial methods. Recent work emphasizes immune–fibroblast crosstalk as a core axis driving fibrosis: immune signals induce fibroblast ECM programs and fibroblasts feed back chemokines that shape immune recruitment. Targeting these communication nodes (cytokines, chemokine axes, matrix sensors) is a promising strategy to tilt repair toward regeneration and away from maladaptive scarring.