c-kit Signaling Inhibits Bone Development by Regulating Skeletal Stem Cell Precursors in Fetal Bone Marrow

c-kit signaling plays pivotal roles in regulating the self-renewal and/or differentiation of many adult stem cells, such as hematopoietic stem cells. However, it remains controversial whether c-kit is expressed by and contribute to skeletal stem cells (SSCs). To test this, we lineage-traced c-kit+ cells and investigated the physiological importance of c-kit+ cells and c-kit signaling in bone development. We found that c-kit was not expressed by postnatal SSCs, but by fetal SSC precursors at the growth cartilage. Lineage-tracing of fetal c-kit+ cells marked approximately 20% of Lepr+ bone marrow stromal cells, generating nearly half of all osteoblasts in adult bone marrow. Disruption of mTOR signaling in c-kit+ cells impaired bone formation. Conditional deletion of Kitl (c-kit ligand, also known as Scf) from fetal, but not adult bone marrow stromal cells increased bone formation. Together, our work identified c-kit+ SSC precursors as an important source of bones formed during development. The osteogenic differentiation of these cells is temporally inhibited by Kitl from the bone marrow microenvironment.