title: Norepinephrine inhibits mesenchymal stem cell chemotaxis migration by increasing stromal cell-derived factor-1 secretion by vascular endothelial cells via NE/abrd3/JNK pathway.
abstract: Mesenchymal stem cells (MSCs), which are physiologically maintained in vascular endothelial cell (VEC)-based niches, play a critical role in tissue regeneration. Our previous studies demonstrated that sympathetic denervation could promote MSC mobilization, thereby enhancing bone formation in distraction osteogenesis (DO), a self-tissue engineering for craniofacial and orthopeadic surgeries. However, the mechanisms on how sympathetic neurotransmitter norepinephrine (NE) regulates MSC migration are not well understood. Here we showed that deprivation of NE by transection of cervical sympathetic trunk (TCST) inhibited stromal cell-derived factor-1 (SDF-1) expression in the perivascular regions in rat mandibular DO. In vitro studies showed that NE treatment markedly upregulated p-JNK and therefore stimulated higher SDF-1 expression in VECs than control groups, and siRNA knockdown of the abrd3 gene abolished the NE-induced p-JNK activation. On the other hand, osteoblasts differentiated from MSCs showed an increase in SDF-1 secretion with lack of NE. Importantly, NE-treated VECs inhibited the MSC chemotaxis migration along the SDF-1 concentration gradient as demonstrated in a novel 3-chamber Transwell assay. Collectively, our study suggested that NE may increase the SDF-1 secretion by VECs via NE/abrd3/JNK pathway, thereby inhibiting the MSC chemotaxis migration from perivascular regions toward bone trabecular frontlines along the SDF-1 concentration gradient in bone regeneration.
authors.affiliation: State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, No.145 West Changle Road, Xi'an 710032, China; No. 3 Hospital of People's Liberation Army, Department of Oral and Maxillofacial Surgery, Baoji 721004, China.
authors.forename: Baolei
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of Oral&Maxillofacial-Head&Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, No.639 Zhizaoju Road, Shanghai 200011, China; State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, No.145 West Changle Road, Xi'an 710032, China. Electronic address: wangleizyh@aliyun.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oral&Maxillofacial-Head&Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, No.639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: No. 3 Hospital of People's Liberation Army, Department of Oral and Maxillofacial Surgery, Baoji 721004, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Oral&Maxillofacial-Head&Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, No.639 Zhizaoju Road, Shanghai 200011, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, No.145 West Changle Road, Xi'an 710032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, No.145 West Changle Road, Xi'an 710032, China.
authors.forename: Zihui
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, No.145 West Changle Road, Xi'an 710032, China.
authors.forename: Xinjie
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, No.145 West Changle Road, Xi'an 710032, China.
authors.forename: Delin
authors.initials: D
authors.lastname: Lei
authors.affiliation: Department of Oral&Maxillofacial-Head&Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, No.639 Zhizaoju Road, Shanghai 200011, China; State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, the Fourth Military Medical University, No.145 West Changle Road, Xi'an 710032, China. Electronic address: zhang.chenping@hotmail.com.
authors.forename: Chenping
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001861:Bone Regeneration / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects* / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley
chemical_list: D054377:Chemokine CXCL12; D009638:Norepinephrine
keywords: Chemotaxis migration; Distraction osteogenesis; Mesenchymal stem cells; Norepinephrine; Stromal cell-derived factor-1; Vascular endothelial cells