Abstract
Hematopoietic stem cell (HSC) fate is tightly controlled by various regulators, whereas the underlying mechanism has not been fully uncovered due to the high heterogeneity of these populations. In this study, we identify tetraspanin CD63 as a novel functional marker of HSCs in mice. We show that CD63 is unevenly expressed on the cell surface in HSC populations. Importantly, HSCs with high CD63 expression (CD63hi) are more quiescent and have more robust self-renewal and myeloid differentiation abilities than those with negative/low CD63 expression (CD63-/lo). On the other hand, using CD63 knockout mice, we find that loss of CD63 leads to reduced HSC numbers in the bone marrow. In addition, CD63-deficient HSCs exhibit impaired quiescence and long-term repopulating capacity, accompanied by increased sensitivity to irradiation and 5-fluorouracil treatment. Further investigations demonstrate that CD63 is required to sustain TGFβ signaling activity through its interaction with TGFβ receptors I and II, thereby playing an important role in regulating the quiescence of HSCs. Collectively, our data not only reveal a previously unrecognized role of CD63 but also provide us with new insights into HSC heterogeneity.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors thank Prof. Jinyong Wang (Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science) for gifting CD45.1 mice, Yang Liu (The Third Military Medical University) for technical support in flow cytometry and Liting Wang (The Third Military Medical University) for technical support in immunofluorescence microscopy.
Funding
This work was supported by grants from the National Natural Science Fund of China (No. 81725019, 81930090, and 81573084) and the Scientific Research Project of PLA (No. ALJ19J002 and AWS16J014).
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M.H. designed the study, performed experiments, analyzed data, and wrote the paper. Y.L., S.W., Z.Z., and Y.Q. performed some experiments and analyzed data. N.C., M.S., and F.C. participated in some in vitro experiments. M.C., L.Y., and S.C. participated data analysis. D.Z., F.W., and Y.S. participated in the initial experimental design and discussed the manuscript. Y.X. and J.W. jointly conceived and supervised the study, and revised the manuscript. All authors read and approved the final paper.
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Hu, M., Lu, Y., Wang, S. et al. CD63 acts as a functional marker in maintaining hematopoietic stem cell quiescence through supporting TGFβ signaling in mice. Cell Death Differ 29, 178–191 (2022). https://doi.org/10.1038/s41418-021-00848-2
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DOI: https://doi.org/10.1038/s41418-021-00848-2
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