1. CYP7B1-mediated 25-hydroxycholesterol degradation maintains quiescence-activation balance and improves therapeutic potential of mesenchymal stem cells.
- Author
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Zhang Z, Su Z, Li Z, Li J, Yu W, Ye G, Lin J, Che Y, Xu P, Zeng Y, Wu Y, Shen H, and Xie Z
- Subjects
- Animals, Humans, Male, Mice, Arthritis, Experimental metabolism, Arthritis, Experimental pathology, Cells, Cultured, Mesenchymal Stem Cell Transplantation, Receptor, Notch3 metabolism, Receptor, Notch3 genetics, Signal Transduction drug effects, Steroid Hydroxylases, Transcription Factor RelA metabolism, Cytochrome P450 Family 7 metabolism, Hydroxycholesterols metabolism, Hydroxycholesterols pharmacology, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells cytology, Mice, Inbred C57BL, Mice, Knockout
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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