A RADICAL SWITCH IN CLONALITY REVEALS THE FORMATION OF A STEM CELL NICHE IN THE EPIPHYSEAL GROWTH PLATE

Abstract

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The majority of disorders affecting final height converge on thin cartilage discs, called growth plates or epiphyseal plates, which are located near the ends of all growing long bones. Growth plates provide a continuous supply of cells that are crucial for the maintenance of normal bone growth. However, how these discs maintain themselves is not known. The generally accepted view is that chondro-progenitors within the growth plate fulfill this function and the consumption of these progenitors leads to the fusion of the growth plate and the cessation of growth. However, this has never been functionally proven. Employing clonal genetic tracing, we show here that in mice longitudinal growth during the fetal and neonatal period occurs via small clones arranged into multi-clonal columns. Such a clonality pattern strongly supports the idea of direct depletion of the progenitors during fetal and neonatal bone growth. In contrast, later in life the clonal pattern drastically changes, with mono-clonal chondrocyte columns formed and a 2-5 fold increase in clone size. This radical switch in clonality suggests that chondro-pro-genitors acquire a capacity to renew themselves, as no other drastic changes in cell kinetics can be observed. Interestingly, this self-renewal behavior coincides with the formation of the secondary ossification center, the expression of stem cell markers and of symmetric cell divisions. Furthermore, we show that these self-renewing progenitors can be expanded by specifically activating the mTORC1-signaling pathway in the growth plate, suggesting a novel target for the development of new treatments of growth disorders. Thus our data suggest that a stem cell niche is formed postnatally in the epiphyseal growth plate and that this niche is essential for the maintenance of postnatal bone growth.