Macrophages in tissue repair and regeneration: insights from zebrafish

Abstract

Macrophages play crucial and versatile roles in regulating tissue repair and regeneration upon injury. However, due to their complex compositional heterogeneity and functional plasticity, deciphering the nature of different macrophage subpopulations and unraveling their dynamics and precise roles during the repair process have been challenging. With its distinct advantages, zebrafish (Danio rerio) has emerged as an invaluable model for studying macrophage development and functions, especially in tissue repair and regeneration, providing valuable insights into our understanding of macrophage biology in health and diseases. In this review, we present the current knowledge and challenges associated with the role of macrophages in tissue repair and regeneration, highlighting the significant contributions made by zebrafish studies. We discuss the unique advantages of the zebrafish model, including its genetic tools, imaging techniques, and regenerative capacities, which have greatly facilitated the investigation of macrophages in these processes. Additionally, we outline the potential of zebrafish research in addressing the remaining challenges and advancing our understanding of the intricate interplay between macrophages and tissue repair and regeneration.

Keywords: Heterogeneity; Inflammation; Macrophage; Ontogeny; Plasticity; Repair and regeneration; Tissue remodeling; Zebrafish.

Fig. 1

Heterogenous ontogeny of RTMs in mice and zebrafish. A RTMs in mice originate from multiple waves of hematopoiesis occurring in distinct hematopoietic tissues during development, including the yolk sac, which produces erythro-myeloid progenitors (EMPs); the fetal liver (FL), which generates a special population of FL-monocytes; and the bone marrow, which gives rise to monocytes. Macrophages from these three waves colonize various tissues and exhibit different replacement kinetic. In the brain, EMP-derived macrophages can self-maintain throughout life and are minimally replaced by macrophages from the other two waves. In the liver, lung alveoli, and epidermis, EMP-derived macrophages are gradually replaced by macrophages derived from FL-monocytes during development, with limited contribution from bone marrow-derived monocytes. However, in the intestine, lung parenchyma, and skin dermis, EMP-derived macrophages are rapidly replaced by macrophages derived from FL monocytes, which are also gradually replaced by macrophages derived from bone marrow monocytes during development. B Similar to mice, RTMs in zebrafish also originate from multiple waves of hematopoiesis occurring in distinct hematopoietic site. During early embryonic development, the rostral blood island (RBI) and posterior blood island (PBI) contribute to the production of transient macrophage progenitor cells (MPs), with RBI-derived macrophages being the predominant population. In addition, definitive hematopoiesis takes place in the ventral wall of the dorsal aorta (VDA), generating HSPCs that migrate to the kidney marrow. The kidney marrow serves as a continuous source of monocytes throughout the lifespan. In most zebrafish tissues, RBI and PBI-derived macrophages are rapidly replaced by macrophages derived from monocytes during development, except in the brain where the replacement of RBI-derived macrophages occurs at a slower rate

Fig. 2

Diverse functions of macrophages during tissue regeneration. This illustration delineates the three main stages of skin wound healing and the key functions of macrophages across these stages. Macrophages perform three primary types of functions: phagocytosis, inflammation regulation, and tissue remodeling. At the inflammation stage, macrophages are responsible for the removal of cell debris (①) and microbes (②) through phagocytosis. Besides, they can stimulate tissue inflammation by releasing pro-inflammatory cytokines and chemokines (③), which leads to the recruitment and activation of other resident immune cells, as well as circulating monocytes and neutrophils. Additionally, macrophages can degrade the ECM to facilitate the infiltration of these recruited cells. Under certain conditions, macrophages can also activate tissue-resident T cells to leverage adaptive immunity for inflammation regulation (④). At the proliferation stage, macrophages promote the differentiation and proliferation of various tissue cells, including epidermal cells, stromal cells, and endothelial cells, through the production of growth factors (⑤). Besides, macrophages can clear apoptotic neutrophils (⑥) and produce anti-inflammatory modulators to resolve tissue inflammation (⑦). At the remodeling stage, macrophages promote the synthesis and deposition of ECM components by regulating the activities of ECM-producing cells such as fibroblast (⑧). They also regulate the formation of ECM structure by releasing ECM-modifying enzymes like MMPs (⑨). Besides, macrophages can guide the formation of neural and vascular networks within the tissues