Combined lineage tracing and scRNA-seq reveal the activation of Sox9 cells in renal regeneration with PGE treatment.

Uncovering mechanisms of endogenous regeneration and repair through resident stem cell activation will allow us to develop specific therapies for injuries and diseases by targeting resident stem cell lineages. Sox9 stem cells have been reported to play an essential role in acute kidney injury (AKI). However, a complete view of the Sox9 lineage was not well investigated to accurately elucidate the functional end state and the choice of cell fate during tissue repair after AKI. To identify the mechanisms of fate determination of Sox9 stem cells, we set up an AKI model with prostaglandin E2 (PGE) treatment in a Sox9 lineage tracing mouse model. Single-cell RNA sequencing (scRNA-seq) was performed to analyse the transcriptomic profile of the Sox9 lineage. Our results revealed that PGE could activate renal Sox9 cells and promote the differentiation of Sox9 cells into renal proximal tubular epithelial cells and inhibit the development of fibrosis. Furthermore, single-cell transcriptome analysis demonstrated that PGE could regulate the restoration of lipid metabolism homeostasis in proximal tubular epithelial cells by participating in communication with different cell types. Our results highlight the prospects for the activation of endogenous renal Sox9 stem cells with PGE for the regenerative therapy of AKI.