Highly efficient induction of Sox9+ scl-progenitors from embryonic stem cells for skeletal modeling

Sclerotomal progenitors derived from pluripotent stem cells hold promises for modeling skeletal development and recapitulating the perinatal marrow niche that may provide insights into hematopoietic niche formation and immune regulation. Current strategy to derive mouse sclerotomal progenitors suffered from low differentiation efficiency and heterogeneous cell progenies. Here, we developed a fast and efficient strategy to generate sclerotomal progenitors by accelerated induction from primitive streak (PS) through modulating BMP and SHH signaling, achieving an 86.9% differentiation efficiency. Moreover, the resulting progenitors showed similar global gene expression profiles to those of the primary sclerotome, possessed strong osteochondral bipotential, and could recapitulate key features of endochondral ossification upon micromass-mediated osteogenic induction, including perinatal bone marrow (BM)-like niches regeneration. Our findings underscore accelerated sclerotomal induction from the primitive streak as an efficient strategy to derive sclerotomal progenitors for skeletal modeling and BM niche bioengineering.