PMID- 38225729 OWN - NLM STAT- MEDLINE DCOM- 20240328 LR - 20240329 IS - 2198-3844 (Electronic) IS - 2198-3844 (Linking) VI - 11 IP - 12 DP - 2024 Mar TI - Tensile Stress-Activated and Exosome-Transferred YAP/TAZ-Notch Circuit Specifies Type H Endothelial Cell for Segmental Bone Regeneration. PG - e2309133 LID - 10.1002/advs.202309133 [doi] LID - 2309133 AB - The Ilizarov technique has been continuously innovated to utilize tensile stress (TS) for inducing a bone development-like regenerative process, aiming to achieve skeletal elongation and reconstruction. However, it remains uncertain whether this distraction osteogenesis (DO) process induced by TS involves the pivotal coupling of angiogenesis and osteogenesis mediated by type H endothelial cells (THECs). In this study, it is demonstrated that the Ilizarov technique induces the formation of a metaphysis-like architecture composed of THECs, leading to segmental bone regeneration during the DO process. Mechanistically, cell-matrix interactions-mediated activation of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcriptionally upregulates the expression of Notch1 and Delta-like ligand 4, which act as direct positive regulators of THECs phenotype, in bone marrow endothelial cells (BMECs) upon TS stimulation. Simultaneously, the Notch intracellular domain enhances YAP/TAZ activity by transcriptionally upregulating YAP expression and stabilizing TAZ protein, thus establishing the YAP/TAZ-Notch circuit. Additionally, TS-stimulated BMECs secrete exosomes enriched with vital molecules in this positive feedback pathway, which can be utilized to promote segmental bone defect healing, mimicking the therapeutic effects of Ilizarov technique. The findings advance the understanding of TS-induced segmental bone regeneration and establish the foundation for innovative biological therapeutic strategies aimed at activating THECs. CI - (c) 2024 The Authors. Advanced Science published by Wiley-VCH GmbH. FAU - Wang, Feng AU - Wang F AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Li, Shanyu AU - Li S AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Kong, Lingchi AU - Kong L AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Feng, Kai AU - Feng K AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Zuo, Rongtai AU - Zuo R AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Zhang, Hanzhe AU - Zhang H AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Yu, Yifan AU - Yu Y AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Zhang, Kunqi AU - Zhang K AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Cao, Yuting AU - Cao Y AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Chai, Yimin AU - Chai Y AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Kang, Qinglin AU - Kang Q AUID- ORCID: 0009-0001-9142-6992 AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. FAU - Xu, Jia AU - Xu J AD - Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. LA - eng GR - 2022YQ005/Shanghai Municipal Health Commission Youth Program/ GR - ynms202104/2021 Basic Scientific Research Cultivation Project of Shanghai Sixth People's Hospital/ GR - 82072421/National Natural Science Foundation of China/ GR - 81930069/National Natural Science Foundation of China/ PT - Journal Article DEP - 20240115 PL - Germany TA - Adv Sci (Weinh) JT - Advanced science (Weinheim, Baden-Wurttemberg, Germany) JID - 101664569 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Trans-Activators) RN - 0 (YAP-Signaling Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (Transcription Factors) SB - IM MH - *Adaptor Proteins, Signal Transducing/genetics MH - Signal Transduction MH - Trans-Activators/metabolism MH - YAP-Signaling Proteins MH - Endothelial Cells/metabolism MH - *Exosomes/metabolism MH - Cell Cycle Proteins/metabolism MH - Transcription Factors/metabolism MH - Bone Regeneration PMC - PMC10966515 OTO - NOTNLM OT - bone formation OT - distraction osteogenesis OT - endothelial cell OT - exosome OT - mechanical force COIS- The authors declare no conflict of interest. EDAT- 2024/01/16 06:42 MHDA- 2024/03/28 06:45 PMCR- 2024/01/15 CRDT- 2024/01/16 00:03 PHST- 2024/01/03 00:00 [revised] PHST- 2023/11/26 00:00 [received] PHST- 2024/03/28 06:45 [medline] PHST- 2024/01/16 06:42 [pubmed] PHST- 2024/01/16 00:03 [entrez] PHST- 2024/01/15 00:00 [pmc-release] AID - ADVS7384 [pii] AID - 10.1002/advs.202309133 [doi] PST - ppublish SO - Adv Sci (Weinh). 2024 Mar;11(12):e2309133. doi: 10.1002/advs.202309133. Epub 2024 Jan 15.