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. 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. 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