Resting zone of the growth plate houses a unique class of skeletal stem cells

Koji Mizuhashi, Wanida Ono, Yuki Matsushita, Naoko Sakagami, Akira Takahashi, Thomas L. Saunders, Takashi Nagasawa, Henry M. Kronenberg and Noriaki Ono ()
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Koji Mizuhashi: University of Michigan School of Dentistry
Wanida Ono: University of Michigan School of Dentistry
Yuki Matsushita: University of Michigan School of Dentistry
Naoko Sakagami: University of Michigan School of Dentistry
Akira Takahashi: University of Michigan School of Dentistry
Thomas L. Saunders: University of Michigan Medical School
Takashi Nagasawa: Graduate School of Frontier Biosciences, Osaka University School of Medicine
Henry M. Kronenberg: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School
Noriaki Ono: University of Michigan School of Dentistry

Nature, 2018, vol. 563, issue 7730, 254-258

Abstract: Abstract 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 plate1–4, 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 zone6–10, 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.

Keywords: Skeletal Stem Cells; Postnatal Growth Plate; Parathyroid Hormone-related Protein (PTHrP); Chondrocyte Columns; Hypertrophic Zone (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (9)

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DOI: 10.1038/s41586-018-0662-5

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