Generation of skeletal cells from pluripotent stem cells

Abstract: Pluripotent stem cell (PSC)-based differentiation systems are a promising tool for in vitro mechanistic studies of developmental processes, disease modeling, drug screening, and stem cell-based therapies. Recent understanding of signaling pathways regulating developmental processes provides us with clues for appropriate inducers for PSC differentiation. We have developed several strategies to generate skeletal cells from mouse and human PSCs under fully defined conditions (Stem Cell Reports, 2014; Sci Adv, 2017; Regen Ther, 2020), based on our previous findings on the Hedgehog signaling-mediated specification of bone-forming cells (Development, 2008; Dev Cell, 2008; J Biol Chem, 2012; J Biol Chem, 2013) and canonical Wnt signaling-directed control of pluripotency and differentiation of PSCs (Stem Cells, 2013). Our strategies are basically composed of three phases: maintenance of PSCs, induction of mesoderm and skeletal progenitors, and differentiation of the progenitor population into skeletal cells. Induction of mesoderm and skeletal progenitors is achieved in vitro under fully defined conditions, where activities of developmentally critical signals are manipulated by small molecules. We have found that the PSC-derived progenitor cells give rise to osteogenic and/or chondrogenic population under appropriate conditions. Thus, the strategies will be a novel platform for biological and pathological studies of skeletal development, screening of therapeutic drugs for the treatment of degenerative skeletal disorders, and regeneration of skeletal tissues.