Junyi Liao1,2, Qiang Wei2,3, Yulong Zou2,3, Jiaming Fan2,3, Dongzhe Song2,4, Jing Cui2,3, Wenwen Zhang2,5, Yunxiao Zhu6, Chao Ma2,7, Xue Hu1,2, Xiangyang Qu2,3, Liqun Chen1,2, Xinyi Yu1,2, Zhicai Zhang2,6, Claire Wang2, Chen Zhao1,2, Zongyue Zeng2,3, Ruyi Zhang2,3, Shujuan Yan2,3, Tingting Wu2,7, Xingye Wu1,2, Yi Shu2,3, Jiayan Lei1,2, Yasha Li2,3, Hue H Luu2, Michael J Lee2, Russell R Reid2,8, Guillermo A Ameer6,9, Jennifer Moriatis Wolf2, Tong-Chuan He2,3, Wei Huang1. 1. Departments of Orthopaedic Surgery, Blood Transfusion, Nephrology, and General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 2. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA. 3. Ministry of Education Key Laboratory of Diagnostic Medicine, and the Affiliated Hospitals of Chongqing Medical University, Chongqing, China. 4. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. 5. Department of Laboratory Medicine and Clinical Diagnostics, the Affiliated Yantai Hospital, Binzhou Medical University, Yantai, China. 6. Biomedical Engineering Department, Northwestern University, Evanston, Illinois, USA. 7. Departments of Neurosurgery and Otolaryngology-Head & Neck Surgery, the Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China. 8. Department of Surgery, Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, Illinois, USA. 9. Department of Surgery, Feinberg School of Medicine, Chicago, Illinois, USA.
Abstract
BACKGROUND/AIMS: Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. METHODS: Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. RESULTS: BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. CONCLUSION: Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It's conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering.
BACKGROUND/AIMS: Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. METHODS: Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. RESULTS:BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. CONCLUSION:Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It's conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering.
Authors: Zhengliang Luo; Xifu Shang; Hao Zhang; Guangxi Wang; Patrick A Massey; Shane R Barton; Christopher G Kevil; Yufeng Dong Journal: Am J Pathol Date: 2019-08 Impact factor: 4.307
Authors: Ling Zhao; Linjuan Huang; Jing Zhang; Jiaming Fan; Fang He; Xia Zhao; Hao Wang; Qing Liu; Deyao Shi; Na Ni; William Wagstaff; Mikhail Pakvasa; Kai Fu; Andrew B Tucker; Connie Chen; Russell R Reid; Rex C Haydon; Hue H Luu; Le Shen; Hongbo Qi; Tong-Chuan He Journal: Am J Transl Res Date: 2020-12-15 Impact factor: 4.060
Authors: Xia Zhao; Bo Huang; Hao Wang; Na Ni; Fang He; Qing Liu; Deyao Shi; Connie Chen; Piao Zhao; Xi Wang; William Wagstaff; Mikhail Pakvasa; Andrew Blake Tucker; Michael J Lee; Jennifer Moriatis Wolf; Russell R Reid; Kelly Hynes; Jason Strelzow; Sherwin H Ho; Tengbo Yu; Jian Yang; Le Shen; Tong-Chuan He; Yongtao Zhang Journal: Am J Transl Res Date: 2021-05-15 Impact factor: 4.060
Authors: Archana Kamalakar; Jay M McKinney; Daniel Salinas Duron; Angelica M Amanso; Samir A Ballestas; Hicham Drissi; Nick J Willett; Pallavi Bhattaram; Andrés J García; Levi B Wood; Steven L Goudy Journal: Bone Date: 2020-09-25 Impact factor: 4.626