an-ectopic-chemokine-expression-model-for-testing-macrophage

An Ectopic Chemokine Expression Model for Testing Macrophage Recruitment In Vivo

Zebrafish are widely used in basic and biomedical research. Many zebrafish transgenic lines are currently available to label various types of cells. Owing ...

Southern Medical University

Current knowledge about the molecular properties and prognostic markers of upper tract urothelial carcinoma (UTUC) is sparse and often based on bladder urothelial carcinoma (UC), which is thought to share common risk factors with UTUC. However, studies have suggested that differences exist regarding tumor behavior and molecular biology of these cancers, comprehensive investigations are needed to guide the clinical management of UTUC. In recent years, massively parallel sequencing has allowed insights into the biology of many cancers, and molecular prognostic markers based on this approach are rapidly emerging. The goal of this study was to characterize the gene expression patterns of UTUC using massively parallel sequencing, and identify potential molecular markers for prognosis in patients with UTUC.

Global gene expression profiling identifies ALDH2, CCNE1 and SMAD3 as potential prognostic markers in upper tract urothelial carcinoma.

Macrophages are key components of the innate immune system and play pivotal roles in immune response, organ development, and tissue homeostasis. Studies in mice and zebrafish have shown that tissue-resident macrophages derived from different hematopoietic origins manifest distinct developmental kinetics and colonization potential, yet the genetic programs controlling the development of macrophages of different origins remain incompletely defined. In this study, we use zebrafish, where tissue-resident macrophages arise from the rostral blood island (RBI) and ventral wall of dorsal aorta (VDA), the zebrafish hematopoietic tissue equivalents to the mouse yolk sac and aorta-gonad-mesonephros for myelopoiesis, to address this issue. We show that RBI- and VDA-born macrophages are orchestrated by distinctive regulatory networks formed by the E-twenty-six (Ets) transcription factors Pu.1 and Spi-b, the zebrafish ortholog of mouse spleen focus forming virus proviral integration oncogene B (SPI-B), and the helix-turn-helix DNA-binding domain containing protein Irf8. Epistatic studies document that during RBI macrophage development, Pu.1 acts upstream of Spi-b, which, upon induction by Pu.1, partially compensates the function of Pu.1. In contrast, Pu.1 and Spi-b act in parallel and cooperatively to regulate the development of VDA-derived macrophages. Interestingly, these two distinct regulatory networks orchestrate the RBI- and VDA-born macrophage development largely by regulating a common downstream gene, Irf8. Our study indicates that macrophages derived from different origins are governed by distinct genetic networks formed by the same repertoire of myeloid-specific transcription factors.

Distinct regulatory networks control the development of macrophages of different origins in zebrafish.

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.

Adult zebrafish Langerhans cells arise from hematopoietic stem/progenitor cells.

Interleukin-34 (IL-34) is a known cytokine that plays an important role in the survival, proliferation, and differentiation of macrophages. In previous studies, IL-34 can induce macrophage migration through syndecan-1 or focal adhesion kinase and extracellular signal-related kinase 1 and 2 pathway. These studies mainly focused on in vitro experiments, but the effect of IL-34 on macrophage migration in vivo is less understood. In our study, we artificially induced macrophage, but not neutrophil, enrichment in the skin or liver by overexpressing IL-34 in epidermal cells or hepatocytes in zebrafish. Live imaging showed that the enrichment of macrophages in the liver is due to the direct attraction of macrophages by IL-34. Our results demonstrated that ectopically expressed IL-34 can induce macrophage migration to liver in vivo.

Article	Year
Global gene expression profiling identifies ALDH2, CCNE1 and SMAD3 as potential prognostic markers in upper tract urothelial carcinoma. BMC cancer\| PubMed ID: 25408144	2014
Distinct regulatory networks control the development of macrophages of different origins in zebrafish. Blood\| PubMed ID: 27940477	2017
Adult zebrafish Langerhans cells arise from hematopoietic stem/progenitor cells. eLife\| PubMed ID: 29905527	2018
Ectopically Expressed IL-34 Can Efficiently Induce Macrophage Migration to the Liver in Zebrafish. Zebrafish\| PubMed ID: 30724719	2019

Jiahao Chen

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