Prx1+ progenitors give rise to new articular cartilage when conditions are permissive for endogenous regeneration.

It is widely acknowledged that articular cartilage lacks the ability to regenerate. However, if such regeneration were possible, which cell type would generate new tissue? The p21^-/- mouse provides an excellent platform to explore this question, hence, we conducted lineage tracing on Paired related homeobox 1 (Prrx1/Prx1) cells post-injury to determine whether endogenous Prx1⁺ cells contribute to regenerated tissues post-injury. p21^-/- mice displayed enhanced endogenous cartilage regeneration, accompanied by notable differences in the number and kinetics of Prx1⁺ cells within and around the injury site. In p21^-/- mice, Prx1⁺ cells underwent chondrogenesis, ultimately contributing to the regenerated articular cartilage layer. These findings underscore the impact of tissue-resident cells on cartilage regeneration, albeit under abnormal conditions. If the conditions within the joint could be manipulated to favor such a regenerative environment, these endogenous cell types might be recruited to facilitate the formation of a new articular cartilage surface post-injury.