1458 Dissection of the molecular and cellular heterogeneity of dermal fibroblasts in skin fibrosis

Skin fibrosis, a common scarring condition that currently has no curative treatments, is caused by persistent activation of fibroblasts after tissue injury or inflammation results in excessive connective deposition, leading to severe disability, organ malfunction and increased morbidity. This study aims uncover the early advanced changes different fibroblast subsets molecular pathways are integral pathological using bleomycin-induced skin fibrosis mouse model recapitulates well human disease. We have shown 2 weeks (early) 4 (advanced) subcutaneous bleomycin injections result an increasing severity characterized dermal thickness, collagen loss adipocytes. performed single cell RNA-sequencing successfully isolated 14944 control, 16344 6860 fibrotic cells. identified subclusters gene signatures altered across time course. Using CellChat, we dissecting specific signaling crosstalk between subpopulations other cells, promoting profibrotic phenotype locking activated state. To understand impact extracellular matrix biomechanics elicit on fate, correlating our histological transcriptomic analysis with nanoindentation atomic force microscopy imaging throughout novel multidisciplinary approach allows us compare cellular lesions, identifying key subpopulations, regulators alterations repair. Our findings will support development new fibroblast-targeted therapies potentially organs.