Angiogenic activity mediates bone repair from human pluripotent stem cell-derived osteogenic cells.

Li Zou,Joan E Bechtold,Zachary Quanbeck,Qingshan Chen,Dan S Kaufman

doi:10.1038/srep22868

Abstract

Human pluripotent stem cells provide a standardized resource for bone repair. However, criteria to determine which exogenous cells best heal orthopedic injuries remain poorly defined. We evaluated osteogenic progenitor cells derived from both human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). Phenotypic and genotypic analyses demonstrated that these hESCs/hiPSCs are similar in their osteogenic differentiation efficiency and they generate osteogenic cells comparable to osteogenic cells derived from mesenchymal stromal cells (BM-MSCs). However, expression of angiogenic factors, such as vascular endothelial growth factor and basic fibroblast growth factor in these osteogenic progenitor cells are markedly different, suggesting distinct pro-angiogenic potential of these stem cell derivatives. Studies to repair a femur non-union fracture demonstrate only osteogenic progenitor cells with higher pro-angiogenic potential significantly enhance bone repair in vivo. Together, these studies highlight a key role of pro-angiogenic potential of transplanted osteogenic cells for effective cell-mediated bone repair.

Highlights

We examined the ability of osteogenic progenitor cells derived from hESCs and hiPSCs of different cell origins to promote bone repair
Using a RUNX2-YFP reporter-integrated hESC line previously used to better characterize hESC-derived osteogenic cells[9], we initially optimized the osteogenic differentiation conditions to demonstrate that culturing these cells with 10% FBS and osteogenic supplements on 0.1% gelatin facilitates hESCs to generate more YFP+(Runx2+)/CD105+ osteogenic progenitor cells compared to other culture conditions (Fig. 1a)
While the expression level of RUNX2 is higher in hESC-OS cells at p1 and p3 than in other two cell lines, and RUNX2 expression is higher in UCBiPSC-OS cells than in PBiPSC-OS at p3, there is no significant difference in gene expression level of RUNX2, OCN and SPARC between the differentiated cells at p5 (Fig. 1c and supplemental Fig. 2)

Summary

Introduction

We examined the ability of osteogenic progenitor cells derived from hESCs and hiPSCs of different cell origins to promote bone repair. Osteogenic phenotypes and expression of key osteogenic genes, as well as production of angiogenic proteins, were compared with osteoprogenitor cells derived from hBM-MSCs in vitro The ability of these hESC, hiPSC, and hBM-MSC-derived osteoprogenitor cells to repair bone in vivo was investigated using a rat femur non-union fracture model. The novel findings in these studies highlight that while the osteogenic cells from different sources have similar osteogenic phenotypes and characteristics in vitro, these cells markedly differ in their ability to promote vascular development in vivo. This pro-angiogenic activity of hESC/hiPSC-derived osteogenic progenitor cells plays a critical role in their ability to mediate effective in vivo repair

Methods

Results

Conclusion