Long-lived chondroprogenitors are generated by fetal-limb Gli1 ⁺ cells and are replenished upon mosaic cell-cycle arrest in the cartilage

Key questions in organ development and regeneration revolve around the origin and regulation factors of the progenitor cells that fuel organ growth ¹ . The cartilage progenitors that drive long-bone growth display a postnatal switch in their behaviour, from short-lived progenitors to self-renewing, long-lived ones ² . However, it is unclear whether these are distinct populations with different origins, or the same population changes over time due to intrinsic/extrinsic factors, or there is no real behavioural switch, just differential proximity to a supportive niche. The multiple candidates of cartilage stem-cell/progenitors that have been recently described add more complexity to this field, as it is unclear how much spatio-temporal overlap there is between these populations. Here, using lineage tracing, single-cell transcriptomics and label-retention assays during normal and compensatory growth, we show that Gli1 ⁺ cells in fetal cartilage are long-lived chondroprogenitors that remain dormant until postnatal stages. Moreover, Pdgfra ⁺ cells outside the cartilage contribute only to short-term chondroprogenitors in normal conditions, but become Gli1-expressing and increase their cartilage contribution in response to cartilage cell-cycle arrest. These findings shed light on the long-standing question of the origin and regulation of long-lived cartilage progenitors, laying the groundwork for potential future approaches to generate cartilage reparative cells in vivo.