the second disease - adapted fibroblast subtype resembled f3: frc - like fibroblasts and upregulated cxcl9 and / or adamdec1 ( fig. 3e ). cxcl9 is a chemoat tractant for cxcr3 cells and has been reported as an activation marker for frcs in lymphoid tissues. ‘ disease-specific ’ fibroblasts ( f6: inflammatory myof ibroblasts, f7: myof ibroblasts and f8: fascia - like myof ibroblasts ) did not have a healthy skin fibroblast counterpart and highly expressed a myof ibroblast gene signature. this myof ibroblast signature included contractility ( acta2 ), extracellular matrix ( ecm ) ( col3a1, col5a1, col8a1, postn and cthrc1 ) and other myof ibroblast - associated genes ( lrrc15, sfrp4, aspn, runx2 and scx ) ( fig. 3c, g and extended data fig. 5d, e ). f6: inflammatory myof ibroblasts additionally expressed immune-related genes such as interleukins ( il11 and il24 ), chemok ines ( cxcl5, cxcl8, cxcl13 and ccl11 ) and matrix metalloproteinases that can remodel tissue to facilitate immune cell infiltration ( mmp1 ) ( fig. 3c ). jak – stat and hypoxic signaling genes were also elevated ( fig. 3h ). f7: myof ibroblasts and f8: fascia - like myof ibroblasts were disting uished by a higher expression of ecm and tgfβ signaling genes, as well as the mechanotransducer piezo2 ( fig. 3c, h ). f8: fascia - like myof ibroblasts were disting uished by expression of f _ fascia - associated genes ( fig. 3c ). overall, our results indicate that healthy fibroblasts can acquire a regenerative phenotype in f1: superficial fibroblasts ( crabp1 cyp27b1 ), a distinc t polarization in f3: frc - like fibroblasts ( cxcl9 / adamdec1 ) and potentially give rise to myof ibroblast states ( acta2 col8a1 sfrp4 ) in diseased skin. we next leveraged the diverse clinical profiles of skin diseases to assess whether fibroblast subtypes provide molecular insights into disease endotypes with respect to scarring. we assigned the 23 skin diseases into three clinically determined risk of scarring groups: low scarring risk, moderate scarring risk, and established scarring / fibrosis ( see methods ) ( fig. 4a ). we excluded neurofibroma from this analysis as it was the only case of benign neoplasia, consisting primarily of f5: schwann - like and f2 / 3: perivascular fibroblasts ( extended data fig. 6a ). we identified distinc t fibroblast compositions for each scarring risk category ( fig. 4b ). low scarring risk diseases were characterized by a high prevalence of f1: superficial ( crabp cyp27b1 ) and f3: frc - like fibroblasts ( cxcl9 / adamdec1 ) ( fig. 4b ), without notable f6 – f8 myof ibroblast populations. this finding agrees with the regenerative - associated gene profile of disease-associated f1: superficial fibroblasts and a role for f3: frc - like fibroblasts in maintaining immune niches. diseases with scarring risk were characterized by a uniquely high prevalence of f6: inflammatory myof ibroblasts, which was not observed in low scarring risk or established fibrosis ( fig. 4b ). f7: myof ibroblasts were observed at a similar prevalence in diseases with scarring risk and established fibrosis. these data point toward f6: inflammatory myof ibroblast as a population influencing scarring risk, but which are largely absent in established fibrosis. f8: fascia - like myof ibroblasts were also elevated in established fibrosis but were predominantly observed in dupuytren contracture, a fibroproliferative disease of the palmar fascia ( fig. 4a ). we used two further approaches to demonstrate the role for distinc t fibroblast subtypes predicting scarring risk. first, we trained a random forest classifier and identified that f6: inflammatory myof ibroblasts and f7: myof ibroblasts were the most important fibroblast subtypes for predicting scarring risk category ( extended data fig. 6b ). second, we profiled a well - recognized myof ibroblast marker ( lrrc15 ) at the protein level. lrrc15 was evident in inflammation with scarring risk ( inflamed hidradenitis suppurativa skin ) but not in noninflamed skin or inflamed skin without scarring risk ( atopic dermatitis skin ) ( fig. 4c ). having established that disease-associated fibroblasts are enriched in distinc t scarring categories, we next used spatial transcriptomics to validate these fibroblast populations in distinc t scarring risk stroma ( fig. 4d – f and supplementary fig. 3 ). in keeping with scrna - seq data ( fig. 4a ), f3: frc - like fibroblasts were expanded in inflamed atopic dermatitis skin ( low risk ), without major myof ibroblasts ( fig. 4d, f and extended data fig. 6c ). we localized the f3: frc - like population to the superficial perivascular immune niche ( fig. 4d ), which we further validated using 10x visium data ( extended data fig. 6d – f ). in melanoma ( scarring risk ), aside from f1, the entire stroma comprised f6: inflammatory myof ibroblasts and f7: myof ibroblasts ( fig. 4e, f and extended data fig. 6g ). f7: myof ibroblasts showed a matrix - producing phenotype ( col1a1, col3a1 and postn ) that characterizes myof ibroblastic cancer - associated fibroblasts ( cafs ) ( myoc afs ). f6: inflammatory myof ibroblasts demonstrated high expression of inflammatory caf ( icaf ) marker genes ( mmp1, mmp3, cxcl8 and il24 ), which was observed in both cancer and inflammatory diseases with scarring risk ( extended data fig. 6h, i ). finally, to complement our analysis of fibroblast proportions by disease, we assessed transcriptomic variability of disease-associated fibroblast subtypes by calculating gene module scores for each disease using defined marker genes to define transcriptomic variability across different disease conditions ( fig. 4g and methods ). the f6: inflammatory myof ibroblast signature score was highest in hidradenitis suppurativa, acne and keratinocytic skin cancers. overall, our findings support distinc t stromal composition in skin diseases associated with differential scarring risk. f6: inflammatory myof ibroblasts were observed in diseases with scarring risk but relatively infrequently observed in established fibrosis, raising the possibility that they may be an intermediate differentiation state toward f7: myof ibroblasts. the differentiation process of healthy fibroblasts into myof ibroblasts remains poorly understood in human tissues despite its clinical relevance. fibroblasts are tissue resident, and thus intermediate states of myof ibroblast differentiation are likely to be captured in the molecular snapshots of skin diseases analyzed. we therefore performed trajectory analysis of fibroblasts in diseased skin to gain further insights into myof ibroblast differentiation, before utilizing time - resolved human wound data as a validation of dynamic changes in stromal composition. we first included all fibroblast subtypes in a partition - based graph abstraction ( paga ) analysis ( extended data fig. 7a ), and then focused further analyses on fibroblast populations found across diseases on hair - bearing and hairless skin ( methods ). f7: myof ibroblasts were a terminally differentiated myof ibroblast state ( fig. 5a – c ), consistent with their presence in established fibrosis. we observed two potential sources for f7: myof ibroblasts in skin across analyses ( fig. 5b, c and extended data fig. 7b ). one trajectory arose directly from the f2: universal lineage. a second trajectory originated from f1: superficial fibroblasts, transitioning to f7: myof ibroblasts via an intermediate f6: inflammatory myof ibroblast state ( fig. 5a – c and extended data fig. 7b ). these two inferred trajectories are consistent with in vivo lineage tracing studies in mice. to investigate these predicted trajectories in real time, we leveraged a human skin wound dataset of 58, 823 cells ( methods ). skin tissue had been collected from healthy human volunteers at baseline ( pre - wound ) and subsequently from healing wounds.