Cardiac fibroblast heterogeneity in cardiac fibrosis implication for cell-type-specific treatment

Figures

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  FIGURE 1. Developmental origins and physiological functions of cardiac fibroblasts. (A) Schematic representation of fibroblast origins. The majority of resident ventricular fibroblasts originate from the pro-epicardial organ (PEO) via epithelial-to-mesenchymal transition (EMT). A secondary population derives from endocardial cells through endothelial-to-mesenchymal transition (EndoMT). (B) Overview of the primary homeostatic functions of cardiac fibroblasts (CFs) in the healthy heart: ECM synthesis and turnover; Mechanosensing and mechanotransduction; Paracrine signaling hub interacting with immune cells (macrophages) and cardiomyocytes; and Electrical coupling with cardiomyocytes via gap junctions to modulate conduction. Epi: epicardium; Endo: endocardium.

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  FIGURE 2. Temporal phases of the cardiac fibroblast response to myocardial infarction. The temporal evolution of fibroblast states following myocardial infarction. The response is categorized into three overlapping phases: Inflammatory Phase (Day 0–3): In response to cardiomyocyte death and the release of DAMPs, fibroblasts adopt a pro-inflammatory “Injury Response” state. These cells secrete cytokines (e.g., IL-6) and chemokines (e.g., Ccl2, Cxcl1) to recruit immune cells such as neutrophils, and express MMPs for initial ECM remodeling. Proliferative and Reparative Phase (Day 3–14): Driven by signals such as TGF-β, fibroblasts differentiate into heterogeneous activated states including Reparative Cardiac Fibroblasts (RCFs) and Myofibroblasts (MYO) that deposit collagen. Macrophage-derived IL-1β may influence the emergence of pathogenic FAP+ activated fibroblasts, which can play a role in maladaptive fibrosis. Maturation and Remodeling Phase (Day 14+): During scar maturation, reparative cells may transition into Matrifibrocytes (MFC), which specialize in maintaining the scar via cross-linked collagen. Conversely, the persistence of CD248+ pathogenic fibroblasts can promote T-cell…

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  FIGURE 3. Targeted Immunotherapeutic Strategies for Reversing Cardiac Fibrosis. The schematic outlines two advanced therapeutic approaches for reversing cardiac fibrosis through the selective depletion of pathogenic fibroblast subsets. Left Panel (Targeting CD248+ Fibroblasts): Depicts a two-step safety-enhanced strategy combining molecular and cellular approaches. First, a biotinylated anti-CD248 antibody is locally injected into the fibrotic heart tissue to specifically tag CD248+ fibroblasts. Subsequently, CD248-BBIR-T cells (Biotin-Binding Immune Receptor-engineered T cells) are administered. These cells are designed to activate strictly upon recognition of the biotin tag, ensuring precise, spatially and temporally controlled depletion of the target fibroblasts to minimize off-target effects. Right Panel (Targeting FAP+ Fibroblasts): Illustrates a theranostic strategy. Imaging Approach: FAP inhibitors for non-invasive Positron Emission Tomography (FAPI-PET) imaging utilizes radiolabeled FAP inhibitors to non-invasively visualize and quantify active fibrosis prior to treatment. Cellular and Molecular Approaches: Therapy involves the elimination of FAP+ fibroblasts via FAP-CAR-T cells.…

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  FIGURE 4. The Macrophage-Fibroblast IL-1β Signaling Axis as a Therapeutic Target in Cardiac Fibrosis. This schematic illustrates the mechanism by which immune cells drive pathological tissue remodeling and identifies specific pharmacological intervention points. Macrophage Activation: The process initiates with activated macrophages (CCR2+), which assemble the intracellular NLRP3 inflammasome. This complex facilitates the processing and secretion of the pro-inflammatory cytokine Interleukin-1β (IL-1β, represented by blue spheres). Fibroblast Differentiation: Secreted IL-1β binds to the IL-1 receptor (IL-1R) on the surface of quiescent fibroblasts. This signaling event acts as a primary switch (indicated by the curved arrow), driving the transition of fibroblasts into an activated, pro-fibrotic phenotype. Pathological Outcome: The activated fibroblasts are characterized by the upregulation of Fibroblast Activation Protein (FAP) and Periostin (POSTN). These cells are responsible for the excessive production and deposition of extracellular.

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  FIGURE 5. Conceptual framework Visualization of Cardiac Fibroblast States. This conceptual framework visualizes cardiac fibroblast heterogeneity as a 2D system defined by two dominant biological programs. The horizontal fibrotic–mechanical axis represents the degree of engagement in contractile and ECM-remodeling programs, ranging from homeostatic states (left) to highly fibrogenic, stiffness-driven states (right). The vertical inflammatory–stress axis represents the level of immune interaction, ranging from minimal immune engagement (bottom) to states explicitly driven by inflammatory cytokines (e.g., IL-1β, NF-κB) or interferon (IFN) signaling (top). Five stable attractor-like meta-states (A–E, large labeled circles) represent coarse-grained phenotype basins: (A) Homeostatic/Reservoir, (B) the central Myofibroblast Core, (C) Scar maintenance, (D) Immune-interactive, and (E) IFN-stressed. Associated marker genes, signaling pathways, niches, and specific fibroblast subtypes from the literature are noted in adjacent boxes. Half-filled circles indicate boundary states carrying mixed features between attractors (e.g., F-Trans/F-Act between A and B; Fibroblast-Clip between B and C). Solid…