Stem cells remain quiescent in vivo and become activated in response to external stimuli. However, the mechanism regulating the quiescence-activation balance of bone-marrow-derived mesenchymal stem cells (BM-MSCs) is still unclear. Herein, we demonstrated that CYP7B1 was the common critical molecule that promoted activation and impeded quiescence of BM-MSCs under inflammatory stimulation. Mechanistically, CYP7B1 degrades 25-hydroxycholesterol (25-HC) into 7α,25-dihydroxycholesterol (7α,25-OHC), which alleviates the quiescence maintenance effect of 25-HC through Notch3 signaling pathway activation. CYP7B1 expression in BM-MSCs was regulated by NF-κB p65 under inflammatory conditions. BM-MSCs from CYP7B1 conditional knockout (CKO) mice had impaired activation abilities, relating to the delayed healing of bone defects. Intravenous infusion of BM-MSCs overexpressing CYP7B1 could improve the pathological scores of mice with collagen-induced arthritis. These results clarified the quiescence-activation regulatory mechanism of BM-MSCs through the NF-κB p65-CYP7B1-Notch3 axis and provided insight into enhancing BM-MSCs biological function as well as the subsequent therapeutic effect.

干细胞在体内保持静止状态，并响应外部刺激而被激活。然而，调节骨髓间充质干细胞（BM-MSCs）静息-激活平衡的机制仍不清楚。在此，我们证明CYP7B1是在炎症刺激下促进BM-MSCs激活并阻止其静止的常见关键分子。从机制上讲，CYP7B1 将 25-羟基胆固醇 (25-HC) 降解为 7α,25-二羟基胆固醇 (7α,25-OHC)，从而通过 Notch3 信号通路激活减轻 25-HC 的静止维持作用。炎症条件下 BM-MSC 中 CYP7B1 的表达受到 NF-κB p65 的调节。来自 CYP7B1 条件敲除 (CKO) 小鼠的 BM-MSC 激活能力受损，这与骨缺损延迟愈合有关。静脉输注过表达 CYP7B1 的 BM-MSC 可以改善胶原诱导关节炎小鼠的病理评分。这些结果阐明了 BM-MSCs 通过 NF-κB p65-CYP7B1-Notch3 轴的静止激活调节机制，为增强 BM-MSCs 的生物学功能以及后续的治疗效果提供了见解。