Effect of the Bone Morphogenetic Protein-2 Doses on the Osteogenic Potential of Human Multipotent Stromal Cells- Containing Tissue Engineered Constructs

Abstract

The addition of bone morphogenetic protein-2 (BMP-2) with multipotent stromal cells (MSC) is an attractive strategy to enhance the bone-forming potential of MSC-based tissue engineering (TE) constructs. However, the effective dosage of BMP-2 remains to be determined. In this study, we evaluated the effects of human MSCs codelivered with BMP-2 at either low or high dosage on the bone-forming potential of constructs in a mice ectopic model. Our results showed that the addition of only low dose of BMP-2 was beneficial to enhance the bone-forming potential of MSCs, whereas high dose of BMP-2 overcame the advantage of combining this growth factor with MSCs. Expressions of select genes of both murine and human origins in TE constructs demonstrated that the beneficial effect of low dose of BMP-2 with implanted human MSCs did not involve enhanced differentiation of these cells into osteoblasts or induction of paracrine cues but rather involved induction of the osteogenic differentiation of the host progenitors. Therefore, the advantage of combining BMP-2 with MSCs to enhance the bone-forming potential of TE constructs appeared to be an additive effect of both components rather than a synergistic one.

Impact Statement

A strategy for improving the efficacy of stem cell-based bone tissue engineering (TE) constructs is to combine bone morphogenetic protein-2 (BMP-2) with multipotent stromal cells (MSC). Previous studies on the potential cooperative effect of BMP-2 with human multipotent stromal cells (hMSCs) on bone formation in vivo have, however, shown contradictory results likely due to the various and/or inappropriate BMP-2 doses. Our results provided evidence that the addition of BMP-2 at low dose only was beneficial to improve the osteogenic potential of hMSCs-containing TE constructs, whereas BMP-2 delivered at high dose overcame the advantage of combining this growth factor with hMSCs. This new knowledge will help in designing improved combination strategies for tissue regeneration with better clinical outcomes.