CD63 acts as a functional marker in maintaining hematopoietic stem cell quiescence through supporting TGFβ signaling in mice

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 (CD63(hi)) 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 TGF beta signaling activity through its interaction with TGF beta 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.

Automated summary

The study identifies CD63 as a novel functional marker of HSCs in mice, showing that high CD63 expression is associated with more quiescent HSCs with robust self-renewal and myeloid differentiation abilities. CD63 deficiency leads to reduced HSC numbers, impaired quiescence, and increased sensitivity to irradiation and 5-fluorouracil treatment. Further investigations reveal that CD63 interacts with TGF beta receptors to sustain TGF beta signaling activity and regulate HSC quiescence.