Fig. 9. FoxA2+ LTSSC maintain cartilage homeostasis by contributing to long-term self-renewal, chondrogenic differentiation and cartilage repair after injury.

FoxA2+ LTSSC, residual from epiphyseal cartilage postnatal development, located on the outskirts of the SOC, contribute to the top compartment of the RZ. FoxA2+ cells are distinct from the short-term PTHrP+ stem cells located at the bottom of the RZ. Prior to P28, FoxA2+ cells have a dual osteo-chondro-progenitor fate, contributing to the chondrogenic lineage (by forming columnar stacks of chondrocytes in the GP), and the osteogenic lineage (by forming col.1+ bone cells in the SOC). After P28, FoxA2+ LTSSC remain mostly in GP, and their contribution to the SOC is reduced. GP injury activates FoxA2+ cells to undergo proliferative expansion and to provide a framework for the regenerating tissue. In conclusion, FoxA2+ cells, located in the top compartment of the RZ, are a PTHrP-(negative) long-term skeletal stem cell (LT-SSC) population necessary for both GP turnover and cartilage regeneration following injury. SOC = secondary ossification center, RZ = resting zone, PZ = proliferating zone, HZ = hypertrophic zone.