Gli1-expressing stromal cells are highly reparative precursors of long-lived chondroprogenitors in the fetal murine limb

The growth-plate cartilage of the developing long bones is a well-known system of spatially segregated stem/progenitor, transient amplifying and terminally differentiated cells. However, the regulation of the number and activity of long-lived cartilage progenitors (LLCPs) is poorly understood, despite its relevance for understanding human-height variation, the evolution of limb size and proportions and the aetiology of skeletal growth disorders. Moreover, whether their behaviour can adapt to developmental perturbations, generating robustness, has not been explored. Here, we show that Gli1⁺ cells are the fetal precursors of postnatal LLCPs, and that Gli1⁺ LLCP precursors remain mostly dormant until postnatal stages. However, in response to genetically-induced cell-cycle arrest targeted to the fetal cartilage, they expand in the cartilage, enabling normal growth. We further show that reparative Gli1⁺ cells originate from Pdgfra⁺ cells outside the cartilage, revealing the surrounding tissues as an unexpected CP source. Elucidating how stromal cells become Gli1⁺ LLCPs could shed light on developmental robustness and lead to growth-boosting therapies.