Therapeutic antibody directed osteogenic differentiation of induced pluripotent stem cell derived MSCs.

Induced pluripotent stem cells (iPSCs) are regarded as a new cell source for regenerative medicine. Recent advances in tissue engineering have brought to light the therapeutic application of induced pluripotent stem cells (iPSCs) in bone defect repair. However, a safe and efficient way to differentiate iPSCs into osteogenic lineage remains to be a major challenge. Here we describe an approach using anti-BMP2 antibodies (Abs) to mediate osteogenic differentiation of iPSC-derived mesenchymal stromal cells (iMSCs). We first proved that 3G7 (an anti-BMP2 Ab) not only bound to BMP2, but also allowed the bound BMP2 to engage the BMP2 receptors on iMSCs. Subcutaneous implantation sites loaded with iMSCs + 3G7 group showed significant bone formation and vascularization in mice while those sites with exogenous BMP2 exhibited dystrophic calcification and significantly lower vascularization. Our in vitro study demonstrated that the anti-BMP2 Ab/BMP2 immune complex were capable of dictating the acquisition of osteogenic phenotype of iMSCs and subsequent mineralization. The study provided the first evidence of antibody-mediated differentiation of iMSCs and osseous regeneration in vivo. This novel strategy takes full advantage of the endogenous bioactive molecules for osseous regeneration and its potential therapeutic application is promising. STATEMENT OF SIGNIFICANCE: Induced pluripotent stem cells (iPSCs) and its derived cells hold significant promise for the treatment of bone defects. In present study, we carried out the concept of antibody-mediated bone regeneration into the iPSC research for the first time. We demonstrated that anti-BMP2 Ab/BMP2 immune complex was capable of promoting osteogenic differentiation of iPSC-derived MSCs (iMSCs), likely through the classical BMP2/Smad1/Runx2 pathway. Subcutaneous co-delivery of iMSCs and anti-BMP2 Abs resulted in significant bone formation and vascularization. These findings suggested antibody mediated osteogenic differentiation may be a favorable approach for iPSC-based bone tissue engineering.