Immune-mediated cardiac development and regeneration

Fig. 1. Development of the mammalian heart, illustrations of the major morphological stages of cardiac development. (A) Cardiac progenitors from the first heart field (FHF) and second heart field (SHF) migrate symmetrically along the midline to form the cardiac crescent. (B) The cardiac crescent fuses to create the linear heart tube. (C) Cardiac looping occurs as the heart tube undergoes asymmetric bending and buckling, establishing the helical shape that precedes chamber formation. (D) Chamber formation progresses alongside septation, which divides the heart into distinct regions, while developing valves regulate blood flow direction. (E) These processes result in the mature four-chambered heart, which uses the cardiac conduction system to coordinate rhythmic contractions that circulate blood throughout the body. (F) Immune cells in human cardiac development. Area plot depicting the changing proportions of distinct immune cell populations throughout human cardiac development (5–26 PCW). Macrophages represent the dominant immune population during early development, with later emergence of additional populations including dendritic cells, T cells and B cells [31]. The dynamic shifts in…

Fig. 2. Specialised immune niches in the developing heart. (A) The valve immune niche undergoes distinct transitions during development. During active remodelling (A’), the niche comprises naïve T cells, dendritic cells, mast cells and MHCIIlow phagocytic macrophages. As valves mature (A”), the immune population shifts toward an antigen-presenting profile with dendritic cells, effector memory T cells and MHCIIhigh macrophages. (B) In the conduction system, CX3CR1+ macrophages establish direct connections with cardiomyocytes through Connexin 43 gap junctions within the atrioventricular node (AVN), enabling coordinated electrical impulse propagation. (C) The epicardial niche functions as a recruitment hub, where epicardial-derived CXCL12 attracts CXCR4-expressing immune cells to establish the subepicardial immune compartment. (D) Within the developing coronary vasculature, MHCIIlow macrophages secrete IGF1 and IGF2 to promote vessel formation, while B cells interact directly with the developing endothelium to support vascular development.

Fig. 3. Immune orchestration of cardiac regeneration. (A) Overview of the regenerative response in species such as zebrafish, where a temporary scar (dark region) is progressively replaced by functional cardiac tissue through immune-mediated processes. (B) At the injury border zone, immune cells coordinate scar replacement through multiple mechanisms. Macrophages facilitate cardiomyocyte invasion into the fibrotic region, while regulatory T cells (Tregs) directly contact cardiomyocytes and secrete regenerative factors including PDGFβ, IGF2 and NRG1. (C) The revascularisation process requires precise immune-vascular coordination. Macrophages promote vessel growth through VEGF secretion. (C′) Detailed view of vessel anastomosis, where macrophages directly facilitate the fusion of endothelial tip cells, recapitulating their developmental role in vascular patterning.

Fig. 4. Discovering immune-mediated mechanisms in cardiac development and regeneration. Overview of a multi-step workflow, including generation and integration of multi-modal single cell datasets, providing a detailed view of diverse immune populations within the heart. The integrated single cell data is then combined with spatial information to map immune cell types and their localisation within the cardiac tissue. Building upon this, in silico modelling generates hypotheses about immune cell roles and interactions in regulating cardiac development and regeneration. This iterative approach allows continuous refinement and validation of these predictions through targeted in vitro and in vivo functional testing. By integrating complementary data and experiments, this pipeline aims to uncover immunemediated mechanisms orchestrating cardiac changes over development, homeostasis and regeneration.