Longitudinal bone growth in children is sustained by growth plates, narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification1. However, it remains unknown how this supply is maintained throughout childhood growth. Chondroprogenitors in the resting zone are thought to be gradually consumed as they supply cells for longitudinal growth1,2, but this model has never been proved. Here, using clonal genetic tracing with multicolour reporters and functional perturbations, we demonstrate that longitudinal growth during the fetal and neonatal periods involves depletion of chondroprogenitors, whereas later in life, coinciding with the formation of the secondary ossification centre, chondroprogenitors acquire the capacity for self-renewal, resulting in the formation of large, stable monoclonal columns of chondrocytes. Simultaneously, chondroprogenitors begin to express stem cell markers and undergo symmetric cell division. Regulation of the pool of self-renewing progenitors involves the hedgehog and mammalian target of rapamycin complex 1 (mTORC1) signalling pathways. Our findings indicate that a stem cell niche develops postnatally in the epiphyseal growth plate, which provides a continuous supply of chondrocytes over a prolonged period.

Center for Developmental Genetics and Department of Anesthesiology Stony Brook University Stony Brook NY USA

Center for Hematology and Regenerative Medicine Karolinska Institutet Huddinge Sweden

Department of Biosciences and Nutrition and Center for Innovative Medicine Karolinska Institutet Huddinge Sweden

Department of Developmental Biology Institute of Experimental Medicine The Czech Academy of Sciences Prague Czech Republic

Department of Molecular Neurosciences Center for Brain Research Medical University Vienna Vienna Austria

Department of Neuroscience Karolinska Institutet Stockholm Sweden

Department of Oral Biochemistry Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden

Department of Women's and Children's Health Karolinska Institutet and Pediatric Endocrinology Unit Karolinska University Hospital Stockholm Sweden

Institute for Regenerative Medicine Sechenov 1st Moscow State Medical University Moscow Russian Federation

National Scientific Center of Marine Biology Far Eastern Branch Russian Academy of Sciences Vladivostok Russian Federation

Science for Life Laboratory Department of Gene Technology KTH Royal Institute of Technology Stockholm Sweden

Nat Rev Endocrinol. 2019 May;15(5):254. doi: 10.1038/s41574-019-0189-3. PubMed

Nature. 2019 Mar;567(7747):178-179. doi: 10.1038/d41586-019-00527-w. PubMed

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