Reprogramming of human fibroblasts into osteoblasts by insulin-like growth factor-binding protein 7
Zufu Lu, Joyce Chiu, Lucinda R. Lee, Aaron Schindeler, M.T. Jackson, Yogambha Ramaswamy, Colin R. Dunstan, Philip J. Hogg, Hala Zreiqat
Abstract
Abstract The induced pluripotent stem cell (iPSC) is a promising cell source for tissue regeneration. However, the therapeutic value of iPSC technology is limited due to the complexity of induction protocols and potential risks of teratoma formation. A trans-differentiation approach employing natural factors may allow better control over reprogramming and improved safety. We report here a novel approach to drive trans-differentiation of human fibroblasts into functional osteoblasts using insulin-like growth factor binding protein 7 (IGFBP7). We initially determined that media conditioned by human osteoblasts can induce reprogramming of human fibroblasts to functional osteoblasts. Proteomic analysis identified IGFBP7 as being significantly elevated in media conditioned with osteoblasts compared with those with fibroblasts. Recombinant IGFBP7 induced a phenotypic switch from fibroblasts to osteoblasts. The switch was associated with senescence and dependent on autocrine IL-6 signaling. Our study supports a novel strategy for regenerating bone by using IGFBP7 to trans-differentiate fibroblasts to osteoblasts. Significance statement Bone tissue engineering is a growing field, where cell therapies have considerable translational potential. Current cell-based approaches are constrained by a limited capacity to harvest osteoblasts, mesenchymal stem cells, and a poor osteogenic potential of isolated patient fibroblasts. This study describes an innovative approach for promoting the trans-differentiation of human fibroblasts into functional osteoblasts using a single naturally bioactive protein, insulin growth factor binding protein-7 (IGFBP7). This approach will have significant advantages over other commonly used cell sources, including iPSCs and adult mesenchymal stem cells, and will potentially lead to a shift in the current paradigm of bone regenerative medicine.