BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of mesenchymal stem cells.

Haozhuo Xiao,Xiaoyu Wang,Junyi Liao,Claire Wang,Guangming Dai,Zhenglin Zhu,Wei Huang,Baicheng He,Shengqiang Gao

doi:10.1042/bsr20201262

Abstract

Bone morphogenetic protein (BMP) 9 (BMP9) is one of most potent BMPs in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). Recently, evidence has shown that osteogenesis and angiogenesis are coupled, however, it is unclear whether BMP9 induces MSC differentiation into endothelial-like cells and further promotes blood vessel formation. In the present study, we explored the potential of BMP9-induced angiogenic differentiation of MSCs, and the relationship between BMP9-induced osteogenic and angiogenic differentiation of MSCs. Osteogenic activities and angiogenic differentiation markers were analyzed at mRNA and protein levels. In vivo osteogenic and angiogenic differentiation of MSCs were tested by the ectopic bone formation model. We identified that adenoviral vectors effectively transduced in immortalized mouse embryonic fibroblasts (iMEFs) and expressed BMP9 with high efficiency. We found that BMP9 induces early and late osteogenic differentiation, and it up-regulated osteogenic marker expression in MSCs. Meanwhile, BMP9 induces angiogenic differentiation of MSCs via the expression of vascular endothelial growth factor a (VEGFa) and CD31 at both mRNA and protein levels. CD31-positive cells were also increased with the stimulation of BMP9. The ectopic bone formation tests found that BMP9-induced trabecular bone formation was coupled with the expression of blood vessel formation markers and sinusoid capillary formation. These findings suggest that BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of MSCs.

Highlights

Mesenchymal stem cells (MSCs) are multipotent cells that can undergo self-renewal and hold the potential to differentiate into osteoblastic, myogenic, chondrogenic, and adipogenic lineages [1,2,3]
We identified that hypoxia-inducible factor 1α (Hif 1α)-mediated angiogenic signaling was essential for BMP9-induced osteogenesis of MSCs [30]
The immortalized mouse embryonic fibroblast (iMEF) cells were cultured in a monolayer culture, and 12 h after the passage, recombinant adenoviruses expression GFP or BMP9 were added in the medium

Summary

Introduction

Mesenchymal stem cells (MSCs) are multipotent cells that can undergo self-renewal and hold the potential to differentiate into osteoblastic, myogenic, chondrogenic, and adipogenic lineages [1,2,3]. Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGF-β) superfamily and function as regulators in skeletal development, bone formation, and osteogenic differentiation of stem cell [8,9,10]. In the past decade, underlying mechanisms in BMP9-induced osteogenic differentiation of MSCs have been explored extensively [15], including Notch signaling [16,17,18], TGF-β signaling [19], epidermal growth factor (EGF) [20], classic Wnt signaling [21,22,23], Nell 1 signaling [24], long noncoding RNA H19 (lncRNA H19) [25], insulin-like growth factors (IGFs) [26], all of which were.

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Results

Conclusion