we provide a consensus annotation of skin fibroblasts based on gene expression profiles and spatial locations, and contextualize these findings with fibroblast data from other healthy and diseased human tissues. our scrna - seq and spatial datasets resources are freely available for download and interactive data exploration at https: / / cellatlas. io / studies / skin - fibroblast. we re - processed and integrated 2. 1 million cells from scrna - seq data of adult human skin, comprising 32 datasets and 251 donors ( fig. 1a and supplementary table 1 ) using single - cell variational inference ( scvi ) ( methods ). after quality control, 357, 276 high - quality fibroblasts were selected based on canonical marker gene expression ( fig. 1a and extended data fig. 1a ). in healthy skin, we identified six major fibroblast subtypes based on differential gene expression ( supplementary data fig. 1a and supplementary table 2 ) and pathway enrichment analysis ( extended data fig. 2a and methods ). the six fibroblast subtypes were observed across different covariates ( extended data fig. 1b – g and supplementary note 1 ). complementary spatial transcriptomic methods validated the presence of each of the six fibroblast subtypes and revealed their distinc t microanatomical locations ( fig. 2a – c, extended data figs. 3 and 4 and supplementary fig. 2 ). two of the six fibroblast populations ( f1: superficial ( papillary ) and f2: universal ( reticular ) ) were uniformly present throughout skin at different tissue depths. f1: superficial ( papillary ) fibroblasts localized adjacent to the skin epithelium in the papillary dermis ( fig. 2b, c ) and expressed genes encoding superficial dermal collagens ( col13a1, col18a1 and col23a1 ) and wnt signaling inhibitors ( apcdd1, wif1 and nkd2 ) ( fig. 1c ). a wnt - mediated synergistic interplay between superficial dermal fibroblasts and basal epithelial cells has been reported to reciprocally maintain cellular identity. f2: universal ( reticular ) fibroblasts were located deeper in the skin, interspersed between large collagen fibers in the reticular dermis ( fig. 2b, c ). this population was characterized by high expression of marker genes of universal pi16 fibroblasts ( pi16, cd34 and mfap5 ), a fibroblast subtype found in many human tissues and postulated to represent a precursor fibroblast cell state. transcription factor activity inference identified klf5 in f2: universal fibroblasts ( extended data fig. 2b ), which has been reported to drive the universal pi16 state. as fascial fibroblasts ( f _ fascia ) are proposed as a potential progenitor cell in mouse skin, we included these cells in an additional integration, identifying that f _ fascia formed a subset of f2: universal ( extended data fig. 1i, j and supplementary note 2 ). the remaining fibroblast subsets were more focal in localization, being associated with vascular or adnexal structures. we thus used hematoxylin and eosin ( h & e ) staining to illustrate these microenvironments. f3: fibroblastic reticular cell ( frc ) - like fibroblasts were located predominantly in the superficial perivascular region in proximity to immune cells ( fig. 2b and extended data figs. 3a, b and 4a, b ). f3: frc - like fibroblasts transcriptomically resembled frcs, which are specialized fibroblasts found in lymphoid organs / structures that maintain immune niches ( extended data fig. 1h ), expressing genes that attract and compartmentalize immune cells ( ccl19, cxcl12 and ch25h ), maintain immune cell survival and function ( il33, il15, tnfsf13b and vcam1 ) and enable antigen presentation ( cd74 and major histocompatibility complex ( mhc ) - ii molecules ). f2 / 3: perivascular fibroblasts also localized with immune cells but, unlike f3: frc - like fibroblasts, were additionally enriched in deep perivascular regions and other sites ( fig. 2a – c and extended data fig. 4b, c ). a fraction of f2 / 3: perivascular fibroblasts showed elevated expression of pparg ( fig. 1c ) and pathway analysis suggested a role in adipocyte differentiation ( extended data fig. 2a ). the capability to differentiate into adipocytes is characteristic of the reticular fibroblast ( equivalent to f2: universal ) lineage. f2 / 3: perivascular fibroblasts shared select gene expression with both f2: universal and f3: frc - like fibroblasts ( fig. 3c ). f4: hair follicle - associated fibroblasts ( aspn col11a1 ) encompassed three subclusters that were associated with specific regions of the hair follicle ( fig. 2b, c ). the first is a well - characterized dermal sheath ( ds ) population ( f4: ds _ dpep1 ) that wraps around the lower / mid hair follicle ( fig. 2b ). the second is a novel f4: tnn coch subtype, expressing tendon - associated genes ( mkx and tnmd ) and observed at the isthmus ( mid - hair shaft ) ( fig. 2b and extended data fig. 4d ). the third f4: dp _ hhip subtype uniquely expressed dermal papilla marker genes ( corin, hhip, rspo3 and lef1 ). f5: schwann - like fibroblasts ( scn7a, fmo2, fgfbp2 and olfml2a ) contained two subclusters ( f5: ngfr and f5: ramp1 ) ( extended data fig. 1k ). f5: ramp1 fibroblasts were enriched near innervated eccrine glands and expressed genes encoding the receptor complex for the neuropeptide cgrp ( fig. 2b, c and extended data figs. 1l, 3c, d and 4c ), suggesting a possible interface with the nervous system. f5: ngfr colocalized with schwann cells, suggesting that they are a nerve - associated population. fibroblasts have been described in the endone urium and perineurium of nerve fibers from imaging studies, and ‘ schwann - like fibroblasts ’ have recently been reported in human skin scrna - seq data. we confirmed that our six fibroblast subtypes were distinc t from schwann cells and pericytes ( extended data fig. 1j, k and supplementary note 2 ). in addition, we harmonized our skin fibroblast annotation with a previous classification ( supplementary data fig. 1b ). overall, we provide a new framework for healthy human skin fibroblast annotation based on gene expression profiles ( fig. 1 ) and spatial location ( fig. 2 ) that integrates previous fibroblast descriptions in skin and across tissues. our findings of transcriptionally defined fibroblast subtypes in distinc t microanatomical locations suggest a role for regional fibroblasts in supporting distinc t niche functions. we next sought to identify how fibroblast states change in diseased skin. we used scpoli, a deep - learning model for integration and identification of novel cell states in single - cell transcriptome data ( methods ) ( fig. 3a ). we mapped fibroblasts from skin diseases to our healthy / nonlesional f1 – f5 fibroblast reference. out of 190, 756 fibroblasts from diseased states, 121, 167 diseased cells were confidently assigned existing f1 – f5 cell labels ( extended data fig. 5a, b ). the remaining 69, 589 fibroblasts from the disease data were classified as uncertain ( unlabeled ) by scpoli ( fig. 3b ). manual annotation based on differential gene expression ( supplementary data fig. 1c and supplementary table 3 ) and pathway analysis ( extended data fig. 5c ) revealed two ‘ disease - adapted ’ and three ‘ disease-specific ’ fibroblast subtypes ( fig. 3b – f ). ‘ disease - adapted ’ fibroblasts resembled a healthy fibroblast subtype counterpart ( fig. 3e ) and were expanded in disease settings ( fig. 3d ). the first disease - adapted fibroblast subtype resembled f1: superficial fibroblasts in healthy skin ( fig. 3e ). the f1 - like disease population upregulated genes suggestive of regenerative function ( crabp1, cyp26b1 and wnt5a ). crabp1 and cyp26b1 are markers of superficial / upper wound fibroblasts in mice, which are thought to be the source of wound - induced hair follicle neogenesis, and involved in retinoic acid degradation. crabp1 fibroblasts are also associated with regeneration in reindeer skin and early - gestational human skin.