Professor Wen received his Ph.D. in Molecular Cell Biology from the Rockefeller University in 1997 and postdoctoral training with Professor Irving Weissman at Stanford University. He was a Principle Investigator at the Institute of Molecular Agrobiolgy and the Institute of Molecular and Cell Biology, Singapore, until 2007. He subsequently moved to Hong Kong and joined the Department of Biochemistry at the Hong Kong University Science and Technology as an Associate Professor. He is currently a Professor of Division of Life Science at the Hong Kong University Science and Technology.
Swimming Through Dendritic Cell Biology: Insights From Fish Models Changlong Zhao, Guanzhen Lin, Kefan Cheng, Shaoli Hassen, Hongru Pan, Zilong Wen Immunological Reviews, 2025 Dendritic cells (DCs) are central to vertebrate immunity, bridging innate and adaptive responses. While DC biology has been extensively studied in mammals, how this cell population is evolutionarily developed and adapted to the ancient immune system of the non‐mammalian vertebrates remains poorly understood. Fish, the earliest vertebrates with a fully developed adaptive immune system, offer unique opportunities to explore the evolutionary emergence and diversification of DCs. Early studies in fish, relying on conserved phenotypical markers and morphological observations, hinted at the existence of DC‐like populations but lacked definitive validation. Recent advances in single‐cell transcriptomics, combined with powerful genetic resources in model organisms like zebrafish, enable the precise identification and characterization of these cells. In this review, we summarize the historical and current understanding of DCs in fish, with a particular focus on zebrafish studies. We highlight both conserved and species‐specific features of their development and function, and further elaborate on two special DC populations that are unique to fish. By integrating evolutionary immunology with cutting‐edge technologies, zebrafish DC research is poised to provide fundamental insights into antigen‐presenting cell biology.
Dendritic cells in developing and adult zebrafish arise from different origins and display distinct flt3 dependencies Guanzhen Lin, Youqi Wang, Thi Giang Pham, Zilong Wen Development Cambridge, 2025 Dendritic cells (DCs) are key cellular components of the immune system and perform crucial functions in innate and acquired immunity. In mammals, it is generally believed that DCs originate exclusively from hematopoietic stem cells (HSCs). Using a temporal-spatial resolved fate-mapping system, here we show that, in zebrafish, DCs arise from two sources: dorsal aorta-born endothelium-derived hematopoietic progenitors (EHPs) and HSCs. The EHP-derived DCs emerge early, predominantly colonizing the developing thymus during larval stages and diminishing by juvenile stages. In contrast, HSC-derived DCs emerge later and can populate different tissues from late larval stages to adulthood. We further document that the EHP- and HSC-derived DCs display different dependencies on Fms-like tyrosine kinase 3 (Flt3), a pivotal receptor tyrosine kinase crucial for DC development in mammals. Our study reveals the presence of two distinct waves of DC development in zebrafish, each with unique origins and developmental controls.
Macrophages in tissue repair and regeneration: insights from zebrafish Changlong Zhao, Zhiyong Yang, Yunbo Li, Zilong Wen Cell Regeneration, 2024 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.
Interplay of Zeb2a, Id2a and Batf3 regulates microglia and dendritic cell development in the zebrafish brain Linh Thi My Nguyen, Shaoli Hassan, Hongru Pan, Shuting Wu, Zilong Wen Development Cambridge, 2024 In vertebrates, the central nervous system (CNS) harbours various immune cells, including parenchymal microglia, perivascular macrophages and dendritic cells, which act in coordination to establish an immune network to regulate neurogenesis and neural function, and to maintain the homeostasis of the CNS. Recent single cell transcriptomic profiling has revealed that the adult zebrafish CNS contains microglia, plasmacytoid dendritic cells (pDCs) and two conventional dendritic cells (cDCs), ccl35+ cDCs and cnn3a+cDCs. However, how these distinct myeloid cells are established in the adult zebrafish CNS remains incompletely defined. Here, we show that the Inhibitor of DNA binding 2a (Id2a) is essential for the development of pDCs and cDCs but is dispensable for the formation of microglia, whereas the Basic leucine zipper transcription factor ATF-like 3 (Batf3) acts downstream of id2a and is required exclusively for the formation of the cnn3a+ cDC subset. In contrast, the Zinc finger E-box-binding homeobox 2a (Zeb2a) promotes the expansion of microglia and inhibits the DC specification, possibly through repressing id2a expression. Our study unravels the genetic networks that govern the development of microglia and brain-associated DCs in the zebrafish CNS.
The different roles of V-ATPase a subunits in phagocytosis/endocytosis and autophagy Qi Chen, Hanjing Kou, Doris Lou Demy, Wei Liu, Jianchao Li, Zilong Wen, Philippe Herbomel, Zhibin Huang, Wenqing Zhang, Jin Xu Autophagy, 2024 Microglia are specialized macrophages responsible for the clearance of dead neurons and pathogens by phagocytosis and degradation. The degradation requires phagosome maturation and acidification provided by the vesicular- or vacuolar-type H+-translocating adenosine triphosphatase (V-ATPase), which is composed of the cytoplasmic V1 domain and the membrane-embedded Vo domain. The V-ATPase a subunit, an integral part of the Vo domain, has four isoforms in mammals. The functions of different isoforms on phagosome maturation in different cells/species remain controversial. Here we show that mutations of both the V-ATPase Atp6v0a1 and Tcirg1b/Atp6v0a3 subunits lead to the accumulation of phagosomes in zebrafish microglia. However, their mechanisms are different. The V-ATPase Atp6v0a1 subunit is mainly distributed in early and late phagosomes. Defects of this subunit lead to a defective transition from early phagosomes to late phagosomes. In contrast, The V-ATPase Tcirg1b/Atp6v0a3 subunit is primarily located on lysosomes and regulates late phagosome-lysosomal fusion. Defective Tcirg1b/Atp6v0a3, but not Atp6v0a1 subunit leads to reduced acidification and impaired macroautophagy/autophagy in microglia. We further showed that ATP6V0A1/a1 and TCIRG1/a3 subunits in mouse macrophages preferentially located in endosomes and lysosomes, respectively. Blocking these subunits disrupted early-to-late endosome transition and endosome-to-lysosome fusion, respectively. Taken together, our results highlight the essential and conserved roles played by different V-ATPase subunits in multiple steps of phagocytosis and endocytosis across various species.
Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish Wenwei Sun, Meimei Wang, Jun Zhao, Shuang Zhao, Wenchao Zhu, Xiaoting Wu, Feifei Li, Wei Liu, Zhuo Wang, Meng Gao, Yiyue Zhang, Jin Xu, Meijia Zhang, Qiang Wang, Zilong Wen, Juan Shen, Wenqing Zhang, Zhibin Huang Nature Communications, 2023 Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.
Cross-organ single-cell transcriptome profiling reveals macrophage and dendritic cell heterogeneity in zebrafish Qiuxia Zhou, Changlong Zhao, Zhiyong Yang, Rui Qu, Yunbo Li, Yining Fan, Jinlin Tang, Ting Xie, Zilong Wen Cell Reports, 2023 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.
Cell competition for neuron-derived trophic factor controls the turnover and lifespan of microglia Tao Yu, Haoyue Kuang, Xiaohai Wu, Ying Huang, Jianzhong Wang, Zilong Wen Science Advances, 2023 Microglia are brain-resident macrophages capable of long-term maintenance through self-renewal. Yet the mechanism governing the turnover and lifespan of microglia remains unknown. In zebrafish, microglia arise from two sources, rostral blood island (RBI) and aorta-gonad-mesonephros (AGM). The RBI-derived microglia are born early but have a short lifespan and diminish in adulthood, while the AGM-derived microglia emerge later and are capable of long-term maintenance in adulthood. Here, we show that the attenuation of RBI microglia is due to their less competitiveness for neuron-derived interleukin-34 (Il34) caused by age-dependent decline of colony-stimulating factor-1 receptor a ( csf1ra ). Alterations of Il34/Csf1ra levels and removal of AGM microglia revamp the proportion and lifespan of RBI microglia. The csf1ra/CSF1R expression in zebrafish AGM-derived microglia and murine adult microglia also undergo age-dependent decline, leading to the elimination of aged microglia. Our study reveals cell competition as a general mechanism controlling the turnover and lifespan of microglia.
[Forward genetic screening for zebrafish mutants defective in erythropoiesis]. Nan Fang Yi Ke Da Xue Xue Bao Journal of Southern Medical University, 2010
[Forward genetic screening for zebrafish mutants defective in myelopoiesis]. Nan Fang Yi Ke Da Xue Xue Bao Journal of Southern Medical University, 2010
Cellular processing of the interleukin-2 fusion toxin DAB486-IL-2 and efficient delivery of diphtheria fragment a to the cytosol of target cells requires Arg194 Journal of Biological Chemistry, 1990
RECENT SCHOLAR PUBLICATIONS
Fibroblast-directed melanocyte recruitment via Cxcl12–Cxcr4 axis promotes post-inflammatory hyperpigmentation and skin barrier protection in zebrafish S Zhao, S Li, C Zhang, Z Tang, A Zhang, C Huang, K Cheng, T Yu, Y Yan, ... Journal of Genetics and Genomics , 2026 2026
Swimming Through Dendritic Cell Biology: Insights From Fish Models C Zhao, G Lin, K Cheng, S Hassen, H Pan, Z Wen Immunological Reviews 336 (1), e70067 , 2025 2025 Citations: 2
Pu. 1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals Y Wu, W Guo, H Kuang, X Wu, TH Trinh, Y Wang, S Zhao, Z Wen, T Yu Elife 14, RP105788 , 2025 2025 Citations: 5
Bona fide hematopoietic stem cells in zebrafish originate from the supra-intestinal artery S Feng, R Qu, Y He, T Huang, Y Wang, TH Trinh, K Cheng, S Zhao, ... bioRxiv, 2025.05. 20.655066 , 2025 2025
Dendritic cells in developing and adult zebrafish arise from different origins and display distinct flt3 dependencies G Lin, Y Wang, TG Pham, Z Wen Development 152 (4), DEV204410 , 2025 2025 Citations: 5
The different roles of V-ATPase a subunits in phagocytosis/endocytosis and autophagy Q Chen, H Kou, DL Demy, W Liu, J Li, Z Wen, P Herbomel, Z Huang, ... Autophagy 20 (10), 2297-2313 , 2024 2024 Citations: 26
Macrophages in tissue repair and regeneration: insights from zebrafish C Zhao, Z Yang, Y Li, Z Wen Cell Regeneration 13 (1), 12 , 2024 2024 Citations: 30
Styxl2 regulates de novo sarcomere assembly by binding to non-muscle myosin IIs and promoting their degradation X Chen, Y Li, J Xu, Y Cui, Q Wu, H Yin, Y Li, C Gao, L Jiang, H Wang, ... Elife 12, RP87434 , 2024 2024 Citations: 4
Fli1 acts in parallel with Pu. 1 to control macrophage and neutrophil fate in zebrafish A Zhang, J Lu, S Feng, H Yu, T Yu, S Zhao, K Chen, Z Huang, J Xu, JY Qu, ... Journal of genetics and genomics= Yi chuan xue bao 51 (3), 359-362 , 2024 2024 Citations: 2
Interplay of Zeb2a, Id2a and Batf3 regulates microglia and dendritic cell development in the zebrafish brain LTM Nguyen, S Hassan, H Pan, S Wu, Z Wen Development 151 (3), dev201829 , 2024 2024 Citations: 6
Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish W Sun, M Wang, J Zhao, S Zhao, W Zhu, X Wu, F Li, W Liu, Z Wang, ... Nature Communications 14 (1), 5351 , 2023 2023 Citations: 23
Cross-organ single-cell transcriptome profiling reveals macrophage and dendritic cell heterogeneity in zebrafish Q Zhou, C Zhao, Z Yang, R Qu, Y Li, Y Fan, J Tang, T Xie, Z Wen Cell reports 42 (7) , 2023 2023 Citations: 76
Cell competition for neuron-derived trophic factor controls the turnover and lifespan of microglia T Yu, H Kuang, X Wu, Y Huang, J Wang, Z Wen Science advances 9 (24), eadf9790 , 2023 2023 Citations: 19
Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity C Zhao, Y Li, J Tang, Q Zhou, X Lin, Z Wen Cell Reports 42 (5) , 2023 2023 Citations: 10
The ETS transcription factor Spi2 regulates hematopoietic cell development in zebrafish S Zhao, A Zhang, H Zhu, Z Wen Development 149 (19), dev200881 , 2022 2022 Citations: 8
Mafba and Mafbb regulate microglial colonization of zebrafish brain via controlling chemotaxis receptor expression L Lou, T Yu, Y Dai, S Zhao, S Feng, J Xu, Z Wen Proceedings of the National Academy of Sciences 119 (39), e2203273119 , 2022 2022 Citations: 13
Csf1rb regulates definitive hematopoiesis in zebrafish Y Dai, S Wu, C Cao, R Xue, X Luo, Z Wen, J Xu Development 149 (16), dev200534 , 2022 2022 Citations: 8
Hemogenic and aortic endothelium arise from a common hemogenic angioblast precursor and are specified by the Etv2 dosage S Zhao, S Feng, Y Tian, Z Wen Proceedings of the National Academy of Sciences 119 (13), e2119051119 , 2022 2022 Citations: 23
Slc20a1b is essential for hematopoietic stem/progenitor cell expansion in zebrafish J Chen, G Li, J Lian, N Ma, Z Huang, J Li, Z Wen, W Zhang, Y Zhang Science China Life Sciences 64 (12), 2186-2201 , 2021 2021 Citations: 9
De novo germline and somatic variants convergently promote endothelial-to-mesenchymal transition in simplex brain arteriovenous malformation H Li, Y Nam, R Huo, W Fu, B Jiang, Q Zhou, D Song, Y Yang, Y Jiao, ... Circulation research 129 (9), 825-839 , 2021 2021 Citations: 46
MOST CITED SCHOLAR PUBLICATIONS
Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6 Z Zhong, Z Wen, JE Darnell Jr Science 264 (5155), 95-98 , 1994 1994 Citations: 2662
Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation Z Wen, Z Zhong, JE Darnell Cell 82 (2), 241-250 , 1995 1995 Citations: 2647
Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. JF Bromberg, CM Horvath, Z Wen, RD Schreiber, JE Darnell Jr Proceedings of the national academy of sciences 93 (15), 7673-7678 , 1996 1996 Citations: 761
A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. CM Horvath, Z Wen, JE Darnell Genes & development 9 (8), 984-994 , 1995 1995 Citations: 740
Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo Y Li, X Du, C Liu, Z Wen, J Du Developmental cell 23 (6), 1189-1202 , 2012 2012 Citations: 697
Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Z Zhong, Z Wen, JE Darnell Jr Proceedings of the National Academy of Sciences 91 (11), 4806-4810 , 1994 1994 Citations: 611
Mapping of Stat3 serine phosphorylation to a single residue (727) and evidence that serine phosphorylation has no influence on DNA binding of Stat1 and Stat3 Z Wen, JE Darnell Jr Nucleic acids research 25 (11), 2062-2067 , 1997 1997 Citations: 450
Live imaging reveals differing roles of macrophages and neutrophils during zebrafish tail fin regeneration L Li, B Yan, YQ Shi, WQ Zhang, ZL Wen Journal of Biological Chemistry 287 (30), 25353-25360 , 2012 2012 Citations: 401
Distribution of the mammalian Stat gene family in mouse chromosomes NG Copeland, DJ Gilbert, C Schindler, Z Zhong, Z Wen, JE Darnell Jr, ... Genomics 29 (1), 225-228 , 1995 1995 Citations: 322
Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice SY Toh, J Gong, G Du, JZ Li, S Yang, J Ye, H Yao, Y Zhang, B Xue, Q Li, ... PloS one 3 (8), e2890 , 2008 2008 Citations: 304
STAT3 activation by cytokines utilizing gp130 and related transducers involves a secondary modification requiring an H7-sensitive kinase. TG Boulton, Z Zhong, Z Wen, JE Darnell Jr, N Stahl, GD Yancopoulos Proceedings of the National Academy of Sciences 92 (15), 6915-6919 , 1995 1995 Citations: 256
Cideb regulates diet-induced obesity, liver steatosis, and insulin sensitivity by controlling lipogenesis and fatty acid oxidation JZ Li, J Ye, B Xue, J Qi, J Zhang, Z Zhou, Q Li, Z Wen, P Li Diabetes 56 (10), 2523-2532 , 2007 2007 Citations: 217
15,000 unique zebrafish EST clusters and their future use in microarray for profiling gene expression patterns during embryogenesis J Lo, S Lee, M Xu, F Liu, H Ruan, A Eun, Y He, W Ma, W Wang, Z Wen, ... Genome Research 13 (3), 455 , 2003 2003 Citations: 214
Loss of function of def selectively up-regulates Δ113p53 expression to arrest expansion growth of digestive organs in zebrafish J Chen, H Ruan, SM Ng, C Gao, HM Soo, W Wu, Z Zhang, Z Wen, ... Genes & development 19 (23), 2900-2911 , 2005 2005 Citations: 209
Stat1 serine phosphorylation occurs independently of tyrosine phosphorylation and requires an activated Jak2 kinase X Zhu, Z Wen, LZ Xu, JE Darnell Jr Molecular and cellular biology 17 (11), 6618-6623 , 1997 1997 Citations: 207
Temporal-spatial resolution fate mapping reveals distinct origins for embryonic and adult microglia in zebrafish J Xu, L Zhu, S He, Y Wu, W Jin, T Yu, JY Qu, Z Wen Developmental cell 34 (6), 632-641 , 2015 2015 Citations: 206
Migratory path of definitive hematopoietic stem/progenitor cells during zebrafish development H Jin, J Xu, Z Wen Blood, The Journal of the American Society of Hematology 109 (12), 5208-5214 , 2007 2007 Citations: 203
Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver. S Ruff-Jamison, Z Zhong, Z Wen, K Chen, JE Darnell, S Cohen Journal of Biological Chemistry 269 (35), 21933-21935 , 1994 1994 Citations: 200
Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-α-inducible genes M Huang, F Qian, Y Hu, C Ang, Z Li, Z Wen Nature cell biology 4 (10), 774-781 , 2002 2002 Citations: 196
Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis L Li, H Jin, J Xu, Y Shi, Z Wen Blood, The Journal of the American Society of Hematology 117 (4), 1359-1369 , 2011 2011 Citations: 191
