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Induction of functional neutrophils from mouse fibroblasts by thymidine through enhancement of Tet3 activity

Abstract

Neutrophils are derived from bone marrow hematopoietic stem cells (HSCs) and are the largest population among circulating white blood cells in humans, acting as the first line of defense against invading pathogens. Whether neutrophils can be generated by transdifferentiation strategies is unknown. Here, we show that thymidine induces the conversion of mouse fibroblasts to neutrophils. Induced neutrophils (iNeus) showed antibacterial effects and did not undergo malignant transformation in vivo. Importantly, iNeu transplantation cured neutropenia in mice in vivo. Mechanistically, thymidine mediates iNeu conversion by enhancing Tet3 activity. Tet3 initiates the expression of the neutrophil fate decision factors Cebpδ and Rfx1 that drive the transdifferentiation of mouse fibroblasts to neutrophils. Therefore, the induction of functional neutrophils by chemicals may provide a potential therapeutic strategy for patients with neutropenia patients and infectious diseases.Fibroblasts; Neutrophils; Thymidine; Transdifferentiation; Tet3

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Acknowledgements

We thank Yihui Xu, Yan Teng, Zhensheng Xie, Can Peng and Xiang Shi, Xin Wen, Xiaoxiao Zhu and Xing Gao for technical support. We thank J. Li (Cnkingbio Company Ltd., Beijing, China) for technical support.

Funding

This work was supported by the National Key R&D Program of China (2020YFA0803501, 2019YFA0508501, 2021YFF0702802), the National Natural Science Foundation of China (82130088, 31930036, 81921003, 31871494, 92042302, 91940305, 32070533, 81772646), the Beijing Natural Science Foundation (5192018), the Biological Resources Program of Chinese Academy of Sciences (KFJ-BRP-017) and the Strategic Priority Research Programs of the Chinese Academy of Sciences (XDB19030203).

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BY designed and performed the experiments, analyzed the data and wrote the paper. LY, BL, and NL performed the experiments and analyzed the data. DF constructed plasmids and established the mouse tools. HL, LS, YD and SW analyzed the data. YT designed the animal experiments and analyzed the data. ZF initiated the study and organized, designed, and wrote the paper.

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Correspondence to Buqing Ye, Yong Tian or Zusen Fan.

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Ye, B., Yang, L., Liu, B. et al. Induction of functional neutrophils from mouse fibroblasts by thymidine through enhancement of Tet3 activity. Cell Mol Immunol 19, 619–633 (2022). https://doi.org/10.1038/s41423-022-00842-9

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