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.
Nature. 2019 Mar;567(7747):234-238. doi: 10.1038/s41586-019-0989-6. Epub 2019 Feb 27.
Longitudinal bone growth in children is sustained by growth plates, narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification. 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 growth, 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.
儿童的骨骼纵向生长是由生长板维持的，生长板是软骨的狭窄圆盘，为软骨内骨化提供源源不断的软骨细胞。然而，目前尚不清楚在整个儿童生长过程中是如何维持这种供应的。静止区的软骨祖细胞被认为随着它们为纵向生长提供细胞而逐渐被消耗，但这一模型从未得到证实。在这里，我们使用多色报告基因的克隆遗传追踪和功能干扰，证明了胎儿和新生儿期的纵向生长涉及软骨祖细胞的耗竭，而在生命的后期，与次生骨化中心的形成同时，软骨祖细胞获得了自我更新的能力，导致形成大的、稳定的单克隆软骨细胞柱。同时，软骨祖细胞开始表达干细胞标志物并进行对称细胞分裂。自我更新祖细胞池的调节涉及 hedgehog 和雷帕霉素靶蛋白复合体 1（mTORC1）信号通路。我们的研究结果表明，一个干细胞龛在出生后在骺板中发育，为软骨细胞提供了一个长时间的持续供应。
