Human skin fibrosis with iPSC-derived organoids reveals RUNX2-mediated fibroblast reprogramming

Fibrotic skin conditions involve continuous fibroblast activation and extracellular matrix changes. The precise regulatory processes behind fibroblast state shifts are not yet fully understood. Researchers created a skin organoid model of fibrosis using human induced pluripotent stem cells (iPSCs) cultured under chronic TGF-β stimulation.

By utilizing single-cell RNA sequencing alongside immunofluorescence-based spatial analysis, they observed dynamic fibroblast state transitions, spatial organization changes, and increased activated fibroblast populations during fibrotic remodeling. Aligning this data with human scleroderma single-cell datasets revealed shared fibroblast states and transcriptional pathways between organoids and patient tissues.

Through this analysis, they identified the broad activation of RUNX2 in the dermal layer during fibrosis. Subsequently, inhibiting RUNX2 reduced fibrotic marker expression. RUNX2 was found to bind to fibrosis-associated genomic regions, encompassing RUNX1 and LOXL2. Employing a machine learning-driven screening method, the scientists discovered a small molecule, F0565-0303, capable of inhibiting RUNX2-mediated fibrotic pathways in vitro and diminishing fibrosis in a bleomycin-induced mouse model.

In summary, these results validate human skin organoids as a tool for studying fibrosis and spotlight RUNX2 as a promising target for therapeutic intervention.