Notch signaling augments BMP9-induced bone formation by promoting the osteogenesis-angiogenesis coupling process in Mesenchymal Stem Cells (MSCs)

Junyi Liao, Qiang Wei, Yulong Zou, Jiaming Fan, Dongzhe Song, Jing Cui, Wenwen Zhang, Yunxiao Zhu, Chao Ma, Xue Hu, Xiangyang Qu, Liqun Chen, Xinyi Yu, Zhicai Zhang, Claire Wang, Chen Zhao, Zongyue Zeng, Ruyi Zhang, Shujuan Yan, Tingting WuXingye Wu, Yi Shu, Jiayan Lei, Yasha Li, Hue H. Luu, Michael J. Lee, Russell R. Reid, Guillermo A. Ameer, Jennifer Moriatis Wolf, Tong Chuan He*, Wei Huang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1905-1923
Number of pages19
JournalCellular Physiology and Biochemistry
Volume41
Issue number5
DOIs
StatePublished - Jun 1 2017

Keywords

  • BMP9 signaling
  • Bone repair
  • Mesenchymal stem cells
  • Notch signaling
  • Osteogenesis-angiogenesis coupling
  • Regenerative medicine

ASJC Scopus subject areas

  • Physiology

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