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Tissue-resident macrophages (TRMs) and dendritic cells (DCs) are highly heterogeneous and essential for immunity, tissue regeneration, and homeostasis maintenance. Here, we comprehensively profile the heterogeneity of TRMs and DCs across adult zebrafish organs via single-cell RNA sequencing. We identify two macrophage subsets: pro-inflammatory macrophages with potent phagocytosis signatures and pro-remodeling macrophages with tissue regeneration signatures in barrier tissues, liver, and heart. In parallel, one conventional dendritic cell (cDC) population with prominent antigen presentation capacity and plasmacytoid dendritic cells (pDCs) featured by anti-virus properties are also observed in these organs. Remarkably, in addition to a single macrophage/microglia population with potent phagocytosis capacity, a pDC population and two distinct cDC populations are identified in the brain. Finally, we generate specific reporter lines for in vivo tracking of macrophage and DC subsets. Our study depicts the landscape of TRMs and DCs and creates valuable tools for in-depth study of these cells in zebrafish. © 2023 The Authors

Metaphocytes are tissue-resident macrophage (TRM)/dendritic cell (DC)-like cells of non-hematopoietic origin in zebrafish barrier tissues. One remarkable property of metaphocytes is their ability to capture soluble antigens from the external environment via transepithelial protrusions, a unique function manifested by specialized subpopulations of the TRMs/DCs in mammal barrier tissues. Yet, how metaphocytes acquire myeloid-like cell properties from non-hematopoietic precursors and how they regulate barrier immunity remains unknown. Here, we show that metaphocytes are in situ generated from local progenitors guided by the ETS transcription factor Spic, the deficiency of which results in the absence of metaphocytes. We further document that metaphocytes are the major IL-22BP-producing cells, and the depletion of metaphocytes causes dysregulated barrier immunity that resembles the phenotype of IL-22BP-deficient mice. These findings reveal the ontogeny, development, and function of metaphocytes in zebrafish, which facilitates our understanding of the nature and function of the mammalian TRM/DC counterparts.

Immune cells in the mucosal barriers of vertebrates are highly heterogeneous in their origin and function. This heterogeneity is further exemplified by the recent discovery of ectoderm-derived immune cells-metaphocytes in zebrafish epidermis. Yet, whether non-hematopoiesis-derived immune cells generally exist in barrier tissues remains obscured. Here, we report the identification and characterization of an endoderm-derived immune cell population in the gill and intestine of zebrafish. Transcriptome analysis reveals that the endoderm-derived immune cells are myeloid-like cells with high similarities to the ectoderm-derived metaphocytes in epidermis. Likemetaphocytes in epidermis, the endoderm-derived immune cells are non-phagocytic but professional in external soluble antigen uptake. Depletion of the endoderm-derived immune cells in gill hinder the local immune response to external soluble stimulants. This study demonstrates a general existence of non-hematopoiesis-derived immune cells in zebrafish mucosal barriers and challenges the prevalent view that resident immune cells in mucosal barriers arise exclusively from hematopoiesis.

Immune cells in the mucosal barriers of vertebrates are highly heterogeneous in their origin and function. This heterogeneity is further exemplified by the recent discovery of ectoderm-derived immune cells-metaphocytes in zebrafish epidermis. Yet, whether non-hematopoiesis-derived immune cells generally exist in barrier tissues remains obscured. Here, we report the identification and characterization of an endoderm-derived immune cell population in the gill and intestine of zebrafish. Transcriptome analysis reveals that the endoderm-derived immune cells are myeloid-like cells with high similarities to the ectoderm-derived metaphocytes in epidermis. Likemetaphocytes in epidermis, the endoderm-derived immune cells are non-phagocytic but professional in external soluble antigen uptake. Depletion of the endoderm-derived immune cells in gill hinder the local immune response to external soluble stimulants. This study demonstrates a general existence of non-hematopoiesis-derived immune cells in zebrafish mucosal barriers and challenges the prevalent view that resident immune cells in mucosal barriers arise exclusively from hematopoiesis.

Immune cells in the mucosal barriers of vertebrates are highly heterogeneous in their origin and function. This heterogeneity is further exemplified by the recent discovery of ectoderm-derived immune cells-metaphocytes in zebrafish epidermis. Yet, whether non-hematopoiesis-derived immune cells generally exist in barrier tissues remains obscured. Here, we report the identification and characterization of an endoderm-derived immune cell population in the gill and intestine of zebrafish. Transcriptome analysis reveals that the endoderm-derived immune cells are myeloid-like cells with high similarities to the ectoderm-derived metaphocytes in epidermis. Likemetaphocytes in epidermis, the endoderm-derived immune cells are non-phagocytic but professional in external soluble antigen uptake. Depletion of the endoderm-derived immune cells in gill hinder the local immune response to external soluble stimulants. This study demonstrates a general existence of non-hematopoiesis-derived immune cells in zebrafish mucosal barriers and challenges the prevalent view that resident immune cells in mucosal barriers arise exclusively from hematopoiesis.

The origin of Langerhans cells (LCs), which are skin epidermis-resident macrophages, remains unclear. Current lineage tracing of LCs largely relies on the promoter-Cre-LoxP system, which often gives rise to contradictory conclusions with different promoters. Thus, reinvestigation with an improved tracing method is necessary. Here, using a laser-mediated temporal-spatial resolved cell labeling method, we demonstrated that most adult LCs originated from the ventral wall of the dorsal aorta (VDA), an equivalent to the mouse aorta, gonads, and mesonephros (AGM), where both hematopoietic stem cells (HSCs) and non-HSC progenitors are generated. Further fine-fate mapping analysis revealed that the appearance of LCs in adult zebrafish was correlated with the development of HSCs, but not T cell progenitors. Finally, we showed that the appearance of tissue-resident macrophages in the brain, liver, heart, and gut of adult zebrafish was also correlated with HSCs. Thus, the results of our study challenged the EMP-origin theory for LCs.

The origin of Langerhans cells (LCs), which are skin epidermis-resident macrophages, remains unclear. Current lineage tracing of LCs largely relies on the promoter-Cre-LoxP system, which often gives rise to contradictory conclusions with different promoters. Thus, reinvestigation with an improved tracing method is necessary. Here, using a laser-mediated temporal-spatial resolved cell labeling method, we demonstrated that most adult LCs originated from the ventral wall of the dorsal aorta (VDA), an equivalent to the mouse aorta, gonads, and mesonephros (AGM), where both hematopoietic stem cells (HSCs) and non-HSC progenitors are generated. Further fine-fate mapping analysis revealed that the appearance of LCs in adult zebrafish was correlated with the development of HSCs, but not T cell progenitors. Finally, we showed that the appearance of tissue-resident macrophages in the brain, liver, heart, and gut of adult zebrafish was also correlated with HSCs. Thus, the results of our study challenged the EMP-origin theory for LCs.

The origin of Langerhans cells (LCs), which are skin epidermis-resident macrophages, remains unclear. Current lineage tracing of LCs largely relies on the promoter-Cre-LoxP system, which often gives rise to contradictory conclusions with different promoters. Thus, reinvestigation with an improved tracing method is necessary. Here, using a laser-mediated temporal-spatial resolved cell labeling method, we demonstrated that most adult LCs originated from the ventral wall of the dorsal aorta (VDA), an equivalent to the mouse aorta, gonads, and mesonephros (AGM), where both hematopoietic stem cells (HSCs) and non-HSC progenitors are generated. Further fine-fate mapping analysis revealed that the appearance of LCs in adult zebrafish was correlated with the development of HSCs, but not T cell progenitors. Finally, we showed that the appearance of tissue-resident macrophages in the brain, liver, heart, and gut of adult zebrafish was also correlated with HSCs. Thus, the results of our study challenged the EMP-origin theory for LCs.

The large Cu-rich deposit is a typical volcanogenic massive sulphide. Thick, large and lenticular orebodies display the stratabound character and there are appreciable density differences between orebodies and country rocks. Ground geophysical methods, especially the gravity method, have proved the most effective for the reconnaissance of hidden massive sulphides. However, the Ashele district is characterised by complex geological structures and the gravity anomalies are usually masked. To solve this problem, orthogonal functions fitted to the Bouguer anomaly were selected for the district which then separated the local gravity anomalies due to the ore horizons from the measured anomalies. A tectono-metallogenic belt was successfully outlined, ore district structures determined, eleven local gravity anomalies were found and the ore prospecting area was charted. It was found that the minimum density of the ores was higher than the maximum density of the country rocks. This shows that gravity anomalies will appear where the ores are., The large Cu-rich deposit is a typical volcanogenic massive sulphide. Thick, large and lenticular orebodies display the stratabound character and there are appreciable density differences between orebodies and country rocks. Ground geophysical methods, especially the gravity method, have proved the most effective for the reconnaissance of hidden massive sulphides. However, the Ashele district is characterised by complex geological structures and the gravity anomalies are usually masked. To solve this problem, orthogonal functions fitted to the Bouguer anomaly were selected for the district which then separated the local gravity anomalies due to the ore horizons from the measured anomalies. A tectono-metallogenic belt was successfully outlined, ore district structures determined, eleven local gravity anomalies were found and the ore prospecting area was charted. It was found that the minimum density of the ores was higher than the maximum density of the country rocks. This shows that gravity anomalies will appear where the ores are.