Following injury, damaged tissues in mammalian organs can either be scarlessly repaired or undergo inefficient regeneration, leading to fibrosis and, potentially, organ failure. In Science, Aggarwal, Wang, Pacheco et al. now report that within the same kidney microenvironment, the difference between scarless recovery and fibrosis depends on the activity of the transcription factor SOX9.

Single-cell RNA sequencing revealed an enrichment of genes involved in the formation and function of polarised tubular epithelia in SOX9on-on cells, including the gene encoding cadherin 6 (CDH6), suggesting an ongoing attempt to regenerate epithelia in tissues that became progressively fibrotic and inflamed. In the regions of successfully regenerated tissue, SOX9 was switched off (SOX9on-off) and remained CDH6-negative.