A cellular trio orchestrating cardiac renewal

Single-cell transcriptomics has unveiled the heterogeneity of cardiac cells, emphasising the complexity of their phenotypes and functions in cardiac homeostasis and repair (1). Furthermore, spatial transcriptomics allows for exploring the intricate interactions among different cell types within tissue niches (2). It has become increasingly apparent that the dynamic communication among cardiomyocytes, fibroblasts, endothelial cells, and immune cells are crucial for cardiac repair. These dynamic cellular interactions promote angiogenesis and stimulate cell proliferation, migration, and survival, as well as the extracellular matrix remodelling and contributing to fibrosis or, as Li et al. demonstrated (3), to cardiac renewal.

This groundbreaking study denotes important progress in understanding the role of cell crosstalk in cardiomyocyte renewal. The authors showed that the activation of YAP within adult cardiomyocytes (aCM2) is crucial for rendering these cells capable of renewal. However, this alone is not enough. The study demonstrates the critical role of a cellular triad composed of aCM2, cardiac fibroblasts expressing the complement pathway component C3, and macrophages expressing the C3a receptor (C3ar1). It shows that the interaction between C3 and C3ar1 is essential for cardiomyocyte differentiation and proliferation. Notably, this triad reflects the pro-renewal environment observed in regenerating neonatal hearts. Interestingly, aCM2 cells with renewal potential are also found in the human heart. Furthermore, the study highlights the significance of anti-fibrotic gene expression in C3+ cardiac fibroblasts.

This work establishes a foundation for future investigations into the heterogeneity of CM, modulation of the cardiac microenvironment and its dynamic changes during different stages and the importance of macrophages as potential renewal and anti-fibrotic therapies. Understanding the nuanced interplay between macrophages and other cardiac cells is critical to developing next-generation therapeutic strategies (4).

Investigating cellular communication, in particular the role of paracrine signalling involving molecules released into the extracellular space by cells as extracellular vesicles or single factors is timely. These molecules play a critical role in modulating the microenvironment and targeting multiple cell types locally. Among these cells are the highly plastic macrophages. Their phenotypic diversity and function are tied to a dynamic response to the microenvironment and are, as demonstrated in Li et al.'s study, influenced by their localisation and neighbour cells. In addition, their phenotype and function in cellular communication have been shown to be affected by priming (5), health status (6) or epigenetics (7) advocating for a nuanced understanding of the cellular interactions and pro-regenerative roles of macrophages.