C-KIT Expression Distinguishes Fetal from Postnatal Skeletal Progenitors

Hematopoietic stem cells (HSCs) and skeletal stem cells (SSCs) cohabit in the bone marrow. KITL (C-KIT ligand) from LEPR(+) adult bone marrow stromal cells is pivotal for HSC maintenance. In contrast, it remains unclear whether KITL/C-KIT signaling also regulates SSCs. Here, we lineage traced C-KIT(+) cells and found that C-KIT was expressed by fetal, but not postnatal skeletal progenitors. Fetal C-KIT(+) cells gave rise to 20% of LEPR(+) stromal cells in adult bone marrow, forming nearly half of all osteoblasts. Disruption of mTOR signaling in fetal C-KIT(+) cells impaired bone formation. Notably, conditional deletion of Kitl from PRX1(+) fetal bone marrow stromal cells, but not LEPR(+) adult bone marrow stromal cells, significantly increased bone formation. Thus, our work identified C-KIT(+) skeletal progenitors as an important source of bones formed during development.