BioProject

The steps governing healing with or without fibrosis within the same microenvironment are unclear. More...

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), the injured proximal tubular epithelial cells activate Sox9 for self-restoration. Using head-to-head comparison of injury- induced Sox9-lineages via spatiotemporal mapping, single-cell sequencing, and single-nuclei chromatin accessibility profiling, we identified a dynamic SOX9 switch. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). In contrast, lineages that maintained Sox9 activity in attempt to regenerate, demarcated by SOX9-induced Cadherin 6 (SOX9on-on CDH6pos ) cell state, generated single-cell Wnt activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses post-injury. Thus, we uncovered a mechanism linking fibrosis to sustained efforts to regenerate the injured tissue. Overall design: RNAseq datasets from FACS-sorted (enriched) control cells that activate Axin2, a reporter of canonical Wnt pathway, "the Wnt responsive cells"; and the myofibroblast population early after kidney ischemia reperfusion injury (IRI) induced AKI. To this end, tamoxifen was administered at d2, and d4 to Axin2CreERT2/+:R26RtdT/+:Acta2-GFP animals, and at d6 dual positive (tdT positive and GFP positive) and tdT negative, GFP positive cells were enriched via FACS. 3 biological replicates. Less...