Efficiency of coculture with angiogenic cells or physiological BMP-2 administration on improving osteogenic differentiation and bone formation of MSCs

Abstract

Cell-based bone regeneration with mesenchymal stem cells (MSCs) represents the current challenge toward repair of bone defects and fractures. The supposed hurdles for satisfactory performance of cell-based constructs include inadequate vascularization and osteogenic signals. Considering the reported beneficial role of angiogenic cells in promoting vascularization and osteogenic differentiation and the osteogenic potential of bone morphogenetic protein 2 (BMP-2), we here evaluated the efficiency of coculture with angiogenic cells or a physiological dose of BMP-2 on improving osteogenic differentiation of MSCs and bone formation in vivo. In three dimensional (3D) collagen hydrogels in vitro, cocultured human umbilical vein endothelial cells (HUVECs) in a 1:1 ratio or with a physiological dose of BMP-2 (2 ng/μL) promoted the osteogenic potential of MSCs evidenced by enhanced alkaline phosphatase activity and gene expression of osteogenic markers. Notably, HUVECs evoked similar osteogenic stimulation as BMP-2, albeit in a delayed manner. When their bone formation capacity was further evaluated in a mouse subcutaneous implantation model, MSCs with BMP-2 demonstrated the highest efficiency with reproducible bone formation. In contrast, MSCs cocultured with HUVECs constructs displayed substantial blood vessel-like structures with fibrous tissue rather than ectopic bone as MSC monoculture controls. Our findings confirm the priority of generating cell-based bone constructs with physiological BMP-2 administration and indicate the potential of using angiogenic cells to develop vascularized constructs. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 643-653, 2019.

Keywords: BMP-2; MSCs; angiogenic cells; bone formation; bone tissue engineering; coculture.