Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs)

Cellular Physiology and Biochemistry - Tập 41 Số 5 - Trang 1905-1923 - 2017
Junyi Liao1,2, Qiang Wei3,2, Yulong Zou3,2, Jiaming Fan3,2, Dongzhe Song2,4, Jing Cui3,2, Wenwen Zhang5,2, Yunxiao Zhu6, Chao Ma7,2, Xue Hu1,2, Xiangyang Qu3,2, Liqun Chen1,2, Xinyi Yu1,2, Zhicai Zhang6,2, Claire Wang2, Chen Zhao1,2, Zongyue Zeng3,2, Ruyi Zhang3,2, Shujuan Yan3,2, Tingting Wu7,2, Xingye Wu1,2, Yi Shu3,2, Jiayan Lei1,2, Yasha Li3,2, Hue H. Luu2, Michael J. Lee2, Russell R. Reid8,2, Guillermo A. Ameer6,9, Jennifer Moriatis Wolf2, Tong‐Chuan He3,2, Wei Huang1
1Departments of Orthopaedic Surgery, Blood Transfusion, Nephrology, and General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
2Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA
3Ministry of Education Key Laboratory of Diagnostic Medicine, and The Affiliated Hospitals of Chongqing Medical University, Chongqing, China
4State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
5Department of Laboratory Medicine and Clinical Diagnostics, the Affiliated Yantai Hospital, Binzhou Medical University, Yantai, China
6Biomedical Engineering Department, Northwestern University, Evanston, IL, USA
7Departments of Neurosurgery and Otolaryngology-Head & Neck Surgery, the Affiliated Zhongnan Hospital of Wuhan University, Wuhan, China
8Department of Surgery, Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL, USA
9Department of Surgery, Feinberg School of Medicine, Chicago, IL, USA

Tóm tắt

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.

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Cellular Physiology and Biochemistry

Tập 41 Số 5

1905-1923

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