Angiogenic and osteogenic regeneration in rats via calcium phosphate scaffold and endothelial cell co-culture with human bone marrow mesenchymal stem cells (MSCs), human umbilical cord MSCs, human induced pluripotent stem cell-derived MSCs and human embryonic stem cell-derived MSCs

Abstract

Angiogenesis is a limiting factor in regenerating large bone defects. The objective of this study was to investigate angiogenic and osteogenic effects of coculture on calcium phosphate cement (CPC) scaffold using human umbilical vein endothelial cells (hUVECs) and mesenchymal stem cells (MSCs) from different origins for the first time. hUVECs were cocultured with four types of cells: human umbilical cord MSCs (hUCMSCs), human bone marrow MSCs (hBMSCs), and MSCs from induced pluripotent stem cells (hiPSC-MSCs) and embryonic stem cells (hESC-MSCs). Constructs were implanted in 8-mm cranial defects of rats for 12 weeks. CPC without cells served as control 1. CPC with hBMSCs served as control 2. Microcapillary-like structures were successfully formed on CPC in vitro in all four cocultured groups. Microcapillary lengths increased with time (p<0.05). Osteogenic and angiogenic gene expressions were highly elevated, and mineralization by cocultured cells increased with time (p<0.05). New bone amount and blood vessel density of cocultured groups were much greater than controls (p<0.05) in an animal study. hUVEC coculture with hUCMSCs, hiPSC-MSCs and hESC-MSCs achieved new bone and vessel density similar to hUVEC coculture with hBMSCs (p>0.1). Therefore, hUCMSCs, hiPSC-MSCs and hESC-MSCs could serve as alternative cell sources to hBMSCs which require an invasive procedure to harvest. In conclusion, this study showed for the first time that cocultures of hUVECs with hUCMSCs, hiPSC-MSCs, hESC-MSCs and hBMSCs delivered via CPC scaffold achieved excellent osteogenic and angiogenic capabilities in vivo. The novel coculture constructs are promising for bone reconstruction with improved angiogenesis for craniofacial/orthopedic applications. Copyright 2017 John Wiley & Sons, Ltd.