Skeletal stem cells regulate bone growth and homeostasis by generating diverse cell types, including chondrocytes, osteoblasts and marrow stromal cells. The emerging concept postulates that there exists a distinct type of skeletal stem cell that is closely associated with the growth plate1,2,3,4, which is a type of cartilaginous tissue that has critical roles in bone elongation5. The resting zone maintains the growth plate by expressing parathyroid hormone-related protein (PTHrP), which interacts with Indian hedgehog (Ihh) that is released from the hypertrophic zone6,7,8,9,10, and provides a source of other chondrocytes11. However, the identity of skeletal stem cells and how they are maintained in the growth plate are unknown. Here we show, in a mouse model, that skeletal stem cells are formed among PTHrP-positive chondrocytes within the resting zone of the postnatal growth plate. PTHrP-positive chondrocytes expressed a panel of markers for skeletal stem and progenitor cells, and uniquely possessed the properties of skeletal stem cells in cultured conditions. Cell-lineage analysis revealed that PTHrP-positive chondrocytes in the resting zone continued to form columnar chondrocytes in the long term; these chondrocytes underwent hypertrophy, and became osteoblasts and marrow stromal cells beneath the growth plate. Transit-amplifying chondrocytes in the proliferating zone—which was concertedly maintained by a forward signal from undifferentiated cells (PTHrP) and a reverse signal from hypertrophic cells (Ihh)—provided instructive cues to maintain the cell fates of PTHrP-positive chondrocytes in the resting zone. Our findings unravel a type of somatic stem cell that is initially unipotent and acquires multipotency at the post-mitotic stage, underscoring the malleable nature of the skeletal cell lineage. This system provides a model in which functionally dedicated stem cells and their niches are specified postnatally, and maintained throughout tissue growth by a tight feedback regulation system.
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Source Data are provided in the online version of the paper. The datasets generated during and/or analysed during the current study are available in Dryad Digital Repository (https://doi.org/10.5061/dryad.3qq5bm7).
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We thank D. Holcomb and M. Curtis of Carl Zeiss Microscopy for assistance in imaging, G. Gavrilina and W. Fillipak of the University of Michigan Transgenic Animal Model Core for assistance with transgenesis. This research was supported by NIH R01DE026666 and R00DE022564 (to N.O.), R03DE027421 (to W.O.), P01DK011794 (to H.M.K.), 2017 Fred F. Schudy Memorial Research Award from the American Association of Orthodontists Foundation (to N.O.) and University of Michigan MCubed 2.0 Grant (to N.O. and W.O.).
Nature thanks O. Klein, M. T. Longaker and the other anonymous reviewer(s) for their contribution to the peer review of this work.