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A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues
Source paper: PMC12479362
|
[
{
"end": 66,
"label": "CellType",
"start": 50,
"text": "skin fibroblasts"
},
{
"end": 117,
"label": "CellType",
"start": 82,
"text": "disease-related fibroblast subtypes"
},
{
"end": 132,
"label": "Tissue",
"start": 125,
"text": "tissues"
}
] |
Single_Cell
|
Fibroblasts sculpt the architecture and cellular microenvironments of various tissues.
|
[
{
"end": 11,
"label": "CellType",
"start": 0,
"text": "Fibroblasts"
},
{
"end": 85,
"label": "Tissue",
"start": 78,
"text": "tissues"
}
] |
Single_Cell
|
Here we constructed a spatially resolved atlas of human skin fibroblasts from healthy skin and 23 skin diseases, with comparison to 14 cross-tissue diseases.
|
[
{
"end": 90,
"label": "Tissue",
"start": 86,
"text": "skin"
},
{
"end": 72,
"label": "CellType",
"start": 50,
"text": "human skin fibroblasts"
}
] |
Single_Cell
|
We define six major skin fibroblast subtypes in health and three that are disease-specific.
|
[
{
"end": 44,
"label": "CellType",
"start": 20,
"text": "skin fibroblast subtypes"
}
] |
Single_Cell
|
We characterize two fibroblast subtypes further as they are conserved across tissues and are immune-related.
|
[
{
"end": 39,
"label": "CellType",
"start": 20,
"text": "fibroblast subtypes"
},
{
"end": 84,
"label": "Tissue",
"start": 77,
"text": "tissues"
}
] |
Single_Cell
|
The first, F3: fibroblastic reticular cell-like fibroblast ( CCL19 CD74 HLA-DRA ), is a fibroblastic reticular cell-like subtype that is predicted to maintain the superficial perivascular immune niche.
|
[
{
"end": 58,
"label": "CellType",
"start": 15,
"text": "fibroblastic reticular cell-like fibroblast"
},
{
"end": 128,
"label": "CellType",
"start": 88,
"text": "fibroblastic reticular cell-like subtype"
},
{
"end": 200,
"label": "Tissue",
"start": 163,
"text": "superficial perivascular immune niche"
}
] |
Single_Cell
|
The second, F6: inflammatory myofibroblasts ( IL11 MMP1 CXCL8 IL7R ), characterizes early human skin wounds, inflammatory diseases with scarring risk and cancer.
|
[
{
"end": 43,
"label": "CellType",
"start": 16,
"text": "inflammatory myofibroblasts"
}
] |
Single_Cell
|
F6: inflammatory myofibroblasts were predicted to recruit neutrophils, monocytes and B cells across multiple human tissues.
|
[
{
"end": 80,
"label": "CellType",
"start": 71,
"text": "monocytes"
},
{
"end": 69,
"label": "CellType",
"start": 58,
"text": "neutrophils"
},
{
"end": 92,
"label": "CellType",
"start": 85,
"text": "B cells"
},
{
"end": 31,
"label": "CellType",
"start": 4,
"text": "inflammatory myofibroblasts"
},
{
"end": 122,
"label": "Tissue",
"start": 115,
"text": "tissues"
}
] |
Single_Cell
|
Our study provides a harmonized nomenclature for skin fibroblasts in health and disease, contextualized with cross-tissue findings and clinical skin disease profiles.
|
[
{
"end": 65,
"label": "CellType",
"start": 49,
"text": "skin fibroblasts"
}
] |
Single_Cell
|
Fibroblasts are crucial cells for shaping tissue architecture and immune cell niches .
|
[
{
"end": 11,
"label": "CellType",
"start": 0,
"text": "Fibroblasts"
},
{
"end": 29,
"label": "CellType",
"start": 24,
"text": "cells"
},
{
"end": 84,
"label": "Tissue",
"start": 66,
"text": "immune cell niches"
}
] |
Single_Cell
|
Studying the heterogeneity of fibroblast subtypes has been challenging due to the scarcity of unique surface markers and their tendency to adopt activated phenotypes during in vitro culture .
|
[
{
"end": 49,
"label": "CellType",
"start": 30,
"text": "fibroblast subtypes"
}
] |
Single_Cell
|
Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics technologies have overcome these challenges, enabling the dissection of fibroblast heterogeneity in human tissues .
|
[
{
"end": 180,
"label": "Tissue",
"start": 167,
"text": "human tissues"
}
] |
Single_Cell
|
While recent studies have described fibroblast states in human skin, they have not spatially resolved their tissue microanatomical location.
|
[
{
"end": 67,
"label": "Tissue",
"start": 57,
"text": "human skin"
}
] |
Single_Cell
|
Very few, if any, have interrogated fibroblasts in diverse disease conditions in the skin and across human tissues .
|
[
{
"end": 47,
"label": "Tissue",
"start": 36,
"text": "fibroblasts"
},
{
"end": 89,
"label": "Tissue",
"start": 85,
"text": "skin"
},
{
"end": 114,
"label": "Tissue",
"start": 101,
"text": "human tissues"
}
] |
Single_Cell
|
Consequently, the fibroblast composition and function in human skin; how it changes across a range of diseases (inflammatory, cancer and fibrosis/scarring); and how these populations relate to other human tissues is still unclear.
|
[
{
"end": 67,
"label": "Tissue",
"start": 57,
"text": "human skin"
},
{
"end": 212,
"label": "Tissue",
"start": 199,
"text": "human tissues"
}
] |
Single_Cell
|
In this study, we integrated published large-scale scRNA-seq datasets of healthy human skin and 23 skin diseases and generated spatial transcriptomics data from two different modalities to construct a high-resolution spatially resolved atlas of more than 350,000 adult human skin fibroblasts.
|
[
{
"end": 91,
"label": "Tissue",
"start": 73,
"text": "healthy human skin"
},
{
"end": 291,
"label": "CellType",
"start": 263,
"text": "adult human skin fibroblasts"
}
] |
Single_Cell
|
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.
|
[
{
"end": 53,
"label": "CellType",
"start": 37,
"text": "skin fibroblasts"
},
{
"end": 210,
"label": "Tissue",
"start": 176,
"text": "healthy and diseased human tissues"
}
] |
Single_Cell
|
Our scRNA-seq and spatial datasets resources are freely available for download and interactive data exploration at https://cellatlas.io/studies/skin-fibroblast .
|
[] |
Single_Cell
|
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 ) .
|
[
{
"end": 48,
"label": "CellType",
"start": 43,
"text": "cells"
},
{
"end": 88,
"label": "Tissue",
"start": 72,
"text": "adult human skin"
}
] |
Single_Cell
|
After quality control, 357,276 high-quality fibroblasts were selected based on canonical marker gene expression (Fig. 1a and Extended Data Fig. 1a ).
|
[
{
"end": 55,
"label": "CellType",
"start": 44,
"text": "fibroblasts"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 60,
"label": "CellType",
"start": 41,
"text": "fibroblast subtypes"
},
{
"end": 15,
"label": "Tissue",
"start": 3,
"text": "healthy skin"
}
] |
Single_Cell
|
The six fibroblast subtypes were observed across different covariates (Extended Data Fig. 1b–g and Supplementary Note 1 ).
|
[
{
"end": 27,
"label": "CellType",
"start": 8,
"text": "fibroblast subtypes"
}
] |
Single_Cell
|
Complementary spatial transcriptomic methods validated the presence of each of the six fibroblast subtypes and revealed their distinct microanatomical locations (Fig. 2a–c , Extended Data Figs. 3 and 4 and Supplementary Fig. 2 ).
|
[
{
"end": 106,
"label": "CellType",
"start": 87,
"text": "fibroblast subtypes"
}
] |
Single_Cell
|
Two of the six fibroblast populations (F1: superficial (papillary) and F2: universal (reticular)) were uniformly present throughout skin at different tissue depths.
|
[
{
"end": 136,
"label": "Tissue",
"start": 132,
"text": "skin"
},
{
"end": 37,
"label": "CellType",
"start": 11,
"text": "six fibroblast populations"
},
{
"end": 66,
"label": "CellType",
"start": 43,
"text": "superficial (papillary)"
},
{
"end": 96,
"label": "CellType",
"start": 75,
"text": "universal (reticular)"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 39,
"label": "CellType",
"start": 4,
"text": "superficial (papillary) fibroblasts"
},
{
"end": 81,
"label": "Tissue",
"start": 66,
"text": "skin epithelium"
},
{
"end": 105,
"label": "Tissue",
"start": 89,
"text": "papillary dermis"
}
] |
Single_Cell
|
A Wnt-mediated synergistic interplay between superficial dermal fibroblasts and basal epithelial cells has been reported to reciprocally maintain cellular identity .
|
[
{
"end": 75,
"label": "CellType",
"start": 45,
"text": "superficial dermal fibroblasts"
},
{
"end": 102,
"label": "CellType",
"start": 80,
"text": "basal epithelial cells"
}
] |
Single_Cell
|
F2: universal (reticular) fibroblasts were located deeper in the skin, interspersed between large collagen fibers in the reticular dermis (Fig. 2b,c ).
|
[
{
"end": 69,
"label": "Tissue",
"start": 65,
"text": "skin"
},
{
"end": 37,
"label": "CellType",
"start": 4,
"text": "universal (reticular) fibroblasts"
},
{
"end": 137,
"label": "Tissue",
"start": 121,
"text": "reticular dermis"
}
] |
Single_Cell
|
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 .
|
[
{
"end": 98,
"label": "CellType",
"start": 72,
"text": "universal PI16 fibroblasts"
},
{
"end": 146,
"label": "CellType",
"start": 128,
"text": "fibroblast subtype"
},
{
"end": 174,
"label": "Tissue",
"start": 161,
"text": "human tissues"
}
] |
Single_Cell
|
Transcription factor activity inference identified KLF5 in F2: universal fibroblasts (Extended Data Fig. 2b ), which has been reported to drive the universal Pi16 state .
|
[
{
"end": 84,
"label": "CellType",
"start": 63,
"text": "universal fibroblasts"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 33,
"label": "CellType",
"start": 3,
"text": "fascial fibroblasts (F_Fascia)"
},
{
"end": 91,
"label": "Tissue",
"start": 81,
"text": "mouse skin"
},
{
"end": 173,
"label": "CellType",
"start": 165,
"text": "F_Fascia"
},
{
"end": 77,
"label": "CellType",
"start": 52,
"text": "potential progenitor cell"
}
] |
Single_Cell
|
The remaining fibroblast subsets were more focal in localization, being associated with vascular or adnexal structures.
|
[
{
"end": 32,
"label": "CellType",
"start": 14,
"text": "fibroblast subsets"
},
{
"end": 118,
"label": "Tissue",
"start": 88,
"text": "vascular or adnexal structures"
}
] |
Single_Cell
|
We thus used hematoxylin and eosin (H&E) staining to illustrate these microenvironments.
|
[] |
Single_Cell
|
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 ).
|
[
{
"end": 54,
"label": "CellType",
"start": 4,
"text": "fibroblastic reticular cell (FRC)-like fibroblasts"
},
{
"end": 120,
"label": "Tissue",
"start": 89,
"text": "superficial perivascular region"
},
{
"end": 149,
"label": "CellType",
"start": 137,
"text": "immune cells"
}
] |
Single_Cell
|
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) .
|
[
{
"end": 24,
"label": "CellType",
"start": 4,
"text": "FRC-like fibroblasts"
},
{
"end": 58,
"label": "CellType",
"start": 54,
"text": "FRCs"
},
{
"end": 93,
"label": "CellType",
"start": 70,
"text": "specialized fibroblasts"
},
{
"end": 129,
"label": "Tissue",
"start": 103,
"text": "lymphoid organs/structures"
},
{
"end": 157,
"label": "Tissue",
"start": 144,
"text": "immune niches"
},
{
"end": 248,
"label": "CellType",
"start": 236,
"text": "immune cells"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 63,
"label": "CellType",
"start": 51,
"text": "immune cells"
},
{
"end": 157,
"label": "Tissue",
"start": 132,
"text": "deep perivascular regions"
},
{
"end": 30,
"label": "CellType",
"start": 6,
"text": "perivascular fibroblasts"
},
{
"end": 100,
"label": "CellType",
"start": 80,
"text": "FRC-like fibroblasts"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 44,
"label": "CellType",
"start": 20,
"text": "perivascular fibroblasts"
}
] |
Single_Cell
|
The capability to differentiate into adipocytes is characteristic of the reticular fibroblast (equivalent to F2: universal) lineage .
|
[
{
"end": 47,
"label": "CellType",
"start": 37,
"text": "adipocytes"
},
{
"end": 93,
"label": "CellType",
"start": 73,
"text": "reticular fibroblast"
},
{
"end": 131,
"label": "CellType",
"start": 113,
"text": "universal) lineage"
}
] |
Single_Cell
|
F2/3: perivascular fibroblasts shared select gene expression with both F2: universal and F3: FRC-like fibroblasts (Fig. 3c ).
|
[
{
"end": 30,
"label": "CellType",
"start": 6,
"text": "perivascular fibroblasts"
},
{
"end": 113,
"label": "CellType",
"start": 93,
"text": "FRC-like fibroblasts"
}
] |
Single_Cell
|
F4: hair follicle-associated fibroblasts ( ASPN COL11A1 ) encompassed three subclusters that were associated with specific regions of the hair follicle (Fig. 2b,c ).
|
[
{
"end": 151,
"label": "Tissue",
"start": 138,
"text": "hair follicle"
},
{
"end": 40,
"label": "CellType",
"start": 4,
"text": "hair follicle-associated fibroblasts"
}
] |
Single_Cell
|
The first is a well-characterized dermal sheath (DS) population (F4: DS_DPEP1 ) that wraps around the lower/mid hair follicle (Fig. 2b ).
|
[
{
"end": 125,
"label": "Tissue",
"start": 112,
"text": "hair follicle"
},
{
"end": 63,
"label": "CellType",
"start": 34,
"text": "dermal sheath (DS) population"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 140,
"label": "Tissue",
"start": 116,
"text": "isthmus (mid-hair shaft)"
},
{
"end": 42,
"label": "CellType",
"start": 26,
"text": "TNN COCH subtype"
}
] |
Single_Cell
|
The third F4: DP_HHIP subtype uniquely expressed dermal papilla marker genes ( CORIN , HHIP , RSPO3 and LEF1 ) .
|
[
{
"end": 29,
"label": "CellType",
"start": 14,
"text": "DP_HHIP subtype"
}
] |
Single_Cell
|
F5: Schwann-like fibroblasts (SCN7A, FMO2 , FGFBP2 and OLFML2A ) contained two subclusters (F5: NGFR and F5: RAMP1 ) (Extended Data Fig. 1k ) .
|
[
{
"end": 28,
"label": "CellType",
"start": 4,
"text": "Schwann-like fibroblasts"
},
{
"end": 100,
"label": "CellType",
"start": 92,
"text": "F5: NGFR"
},
{
"end": 114,
"label": "CellType",
"start": 105,
"text": "F5: RAMP1"
}
] |
Single_Cell
|
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.
|
[
{
"end": 253,
"label": "Tissue",
"start": 239,
"text": "nervous system"
},
{
"end": 21,
"label": "CellType",
"start": 4,
"text": "RAMP1 fibroblasts"
},
{
"end": 66,
"label": "Tissue",
"start": 41,
"text": "innervated eccrine glands"
}
] |
Single_Cell
|
F5: NGFR colocalized with Schwann cells, suggesting that they are a nerve-associated population.
|
[
{
"end": 8,
"label": "CellType",
"start": 0,
"text": "F5: NGFR"
},
{
"end": 39,
"label": "CellType",
"start": 26,
"text": "Schwann cells"
},
{
"end": 95,
"label": "CellType",
"start": 68,
"text": "nerve-associated population"
}
] |
Single_Cell
|
Fibroblasts have been described in the endoneurium and perineurium of nerve fibers from imaging studies , and ‘Schwann-like fibroblasts’ have recently been reported in human skin scRNA-seq data .
|
[
{
"end": 11,
"label": "Tissue",
"start": 0,
"text": "Fibroblasts"
},
{
"end": 50,
"label": "Tissue",
"start": 39,
"text": "endoneurium"
},
{
"end": 82,
"label": "Tissue",
"start": 55,
"text": "perineurium of nerve fibers"
},
{
"end": 135,
"label": "CellType",
"start": 111,
"text": "Schwann-like fibroblasts"
}
] |
Single_Cell
|
We confirmed that our six fibroblast subtypes were distinct from Schwann cells and pericytes (Extended Data Fig. 1j,k and Supplementary Note 2 ).
|
[
{
"end": 92,
"label": "CellType",
"start": 83,
"text": "pericytes"
},
{
"end": 45,
"label": "CellType",
"start": 26,
"text": "fibroblast subtypes"
},
{
"end": 78,
"label": "CellType",
"start": 65,
"text": "Schwann cells"
}
] |
Single_Cell
|
In addition, we harmonized our skin fibroblast annotation with a previous classification (Supplementary Data Fig. 1b ).
|
[] |
Single_Cell
|
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.
|
[
{
"end": 212,
"label": "Tissue",
"start": 208,
"text": "skin"
},
{
"end": 231,
"label": "Tissue",
"start": 224,
"text": "tissues"
}
] |
Single_Cell
|
Our findings of transcriptionally defined fibroblast subtypes in distinct microanatomical locations suggest a role for regional fibroblasts in supporting distinct niche functions.
|
[
{
"end": 61,
"label": "CellType",
"start": 16,
"text": "transcriptionally defined fibroblast subtypes"
},
{
"end": 99,
"label": "Tissue",
"start": 74,
"text": "microanatomical locations"
},
{
"end": 139,
"label": "CellType",
"start": 119,
"text": "regional fibroblasts"
}
] |
Single_Cell
|
We next sought to identify how fibroblast states change in diseased skin.
|
[
{
"end": 72,
"label": "Tissue",
"start": 59,
"text": "diseased skin"
}
] |
Single_Cell
|
We used scPoli , a deep-learning model for integration and identification of novel cell states in single-cell transcriptome data ( Methods ) (Fig. 3a ).
|
[] |
Single_Cell
|
We mapped fibroblasts from skin diseases to our healthy/nonlesional F1–F5 fibroblast reference.
|
[
{
"end": 21,
"label": "CellType",
"start": 10,
"text": "fibroblasts"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 26,
"label": "CellType",
"start": 15,
"text": "fibroblasts"
}
] |
Single_Cell
|
The remaining 69,589 fibroblasts from the disease data were classified as uncertain (unlabeled) by scPoli (Fig. 3b ).
|
[
{
"end": 32,
"label": "CellType",
"start": 21,
"text": "fibroblasts"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 237,
"label": "CellType",
"start": 171,
"text": "‘disease-adapted’ and three ‘disease-specific’ fibroblast subtypes"
}
] |
Single_Cell
|
‘Disease-adapted’ fibroblasts resembled a healthy fibroblast subtype counterpart (Fig. 3e ) and were expanded in disease settings (Fig. 3d ).
|
[
{
"end": 29,
"label": "CellType",
"start": 0,
"text": "‘Disease-adapted’ fibroblasts"
},
{
"end": 68,
"label": "CellType",
"start": 42,
"text": "healthy fibroblast subtype"
}
] |
Single_Cell
|
The first disease-adapted fibroblast subtype resembled F1: superficial fibroblasts in healthy skin (Fig. 3e ).
|
[
{
"end": 44,
"label": "CellType",
"start": 10,
"text": "disease-adapted fibroblast subtype"
},
{
"end": 82,
"label": "CellType",
"start": 55,
"text": "F1: superficial fibroblasts"
},
{
"end": 98,
"label": "Tissue",
"start": 86,
"text": "healthy skin"
}
] |
Single_Cell
|
The F1-like disease population upregulated genes suggestive of regenerative function ( CRABP1 , CYP26B1 and WNT5A ) .
|
[
{
"end": 30,
"label": "CellType",
"start": 4,
"text": "F1-like disease population"
}
] |
Single_Cell
|
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.
|
[
{
"end": 69,
"label": "CellType",
"start": 34,
"text": "superficial/upper wound fibroblasts"
}
] |
Single_Cell
|
CRABP1 fibroblasts are also associated with regeneration in reindeer skin and early-gestational human skin .
|
[
{
"end": 18,
"label": "CellType",
"start": 0,
"text": "CRABP1 fibroblasts"
},
{
"end": 73,
"label": "Tissue",
"start": 60,
"text": "reindeer skin"
},
{
"end": 106,
"label": "Tissue",
"start": 78,
"text": "early-gestational human skin"
}
] |
Single_Cell
|
The second disease-adapted fibroblast subtype resembled F3: FRC-like fibroblasts and upregulated CXCL9 and/or ADAMDEC1 (Fig. 3e ).
|
[
{
"end": 45,
"label": "CellType",
"start": 11,
"text": "disease-adapted fibroblast subtype"
},
{
"end": 80,
"label": "CellType",
"start": 60,
"text": "FRC-like fibroblasts"
}
] |
Single_Cell
|
CXCL9 is a chemoattractant for CXCR3 cells and has been reported as an activation marker for FRCs in lymphoid tissues .
|
[
{
"end": 117,
"label": "Tissue",
"start": 101,
"text": "lymphoid tissues"
},
{
"end": 42,
"label": "CellType",
"start": 31,
"text": "CXCR3 cells"
},
{
"end": 97,
"label": "CellType",
"start": 93,
"text": "FRCs"
}
] |
Single_Cell
|
‘Disease-specific’ fibroblasts (F6: inflammatory myofibroblasts, F7: myofibroblasts and F8: fascia-like myofibroblasts) did not have a healthy skin fibroblast counterpart and highly expressed a myofibroblast gene signature.
|
[
{
"end": 30,
"label": "CellType",
"start": 0,
"text": "‘Disease-specific’ fibroblasts"
},
{
"end": 158,
"label": "CellType",
"start": 135,
"text": "healthy skin fibroblast"
},
{
"end": 63,
"label": "CellType",
"start": 36,
"text": "inflammatory myofibroblasts"
},
{
"end": 83,
"label": "CellType",
"start": 69,
"text": "myofibroblasts"
},
{
"end": 118,
"label": "CellType",
"start": 92,
"text": "fascia-like myofibroblasts"
}
] |
Single_Cell
|
This myofibroblast signature included contractility ( ACTA2 ), extracellular matrix (ECM) ( COL3A1 , COL5A1 , COL8A1 , POSTN and CTHRC1 ) and other myofibroblast-associated genes ( LRRC15 , SFRP4 , ASPN , RUNX2 and SCX ) (Fig. 3c,g and Extended Data Fig. 5d,e ) .
|
[] |
Single_Cell
|
F6: inflammatory myofibroblasts additionally expressed immune-related genes such as interleukins ( IL11 and IL24 ), chemokines ( CXCL5 , CXCL8 , CXCL13 and CCL11 ) and matrix metalloproteinases that can remodel tissue to facilitate immune cell infiltration ( MMP1 ) (Fig. 3c ).
|
[
{
"end": 217,
"label": "Tissue",
"start": 211,
"text": "tissue"
},
{
"end": 31,
"label": "CellType",
"start": 4,
"text": "inflammatory myofibroblasts"
}
] |
Single_Cell
|
JAK–STAT and hypoxic signaling genes were also elevated (Fig. 3h ).
|
[] |
Single_Cell
|
F7: myofibroblasts and F8: fascia-like myofibroblasts were distinguished by a higher expression of ECM and TGFβ signaling genes, as well as the mechanotransducer PIEZO2 (Fig. 3c,h ).
|
[
{
"end": 18,
"label": "CellType",
"start": 4,
"text": "myofibroblasts"
},
{
"end": 53,
"label": "CellType",
"start": 27,
"text": "fascia-like myofibroblasts"
}
] |
Single_Cell
|
F8: fascia-like myofibroblasts were distinguished by expression of F_Fascia-associated genes (Fig. 3c ).
|
[
{
"end": 30,
"label": "CellType",
"start": 4,
"text": "fascia-like myofibroblasts"
}
] |
Single_Cell
|
Overall, our results indicate that healthy fibroblasts can acquire a regenerative phenotype in F1: superficial fibroblasts ( CRABP1 CYP27B1 ), a distinct polarization in F3: FRC-like fibroblasts ( CXCL9 / ADAMDEC1 ) and potentially give rise to myofibroblast states ( ACTA2 COL8A1 SFRP4 ) in diseased skin.
|
[
{
"end": 54,
"label": "CellType",
"start": 35,
"text": "healthy fibroblasts"
},
{
"end": 265,
"label": "CellType",
"start": 245,
"text": "myofibroblast states"
},
{
"end": 305,
"label": "Tissue",
"start": 292,
"text": "diseased skin"
},
{
"end": 122,
"label": "CellType",
"start": 99,
"text": "superficial fibroblasts"
},
{
"end": 194,
"label": "CellType",
"start": 174,
"text": "FRC-like fibroblasts"
}
] |
Single_Cell
|
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.
|
[
{
"end": 102,
"label": "CellType",
"start": 83,
"text": "fibroblast subtypes"
}
] |
Single_Cell
|
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 ).
|
[] |
Single_Cell
|
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 ).
|
[
{
"end": 129,
"label": "CellType",
"start": 117,
"text": "Schwann-like"
},
{
"end": 164,
"label": "CellType",
"start": 140,
"text": "perivascular fibroblasts"
}
] |
Single_Cell
|
We identified distinct fibroblast compositions for each scarring risk category (Fig. 4b ).
|
[] |
Single_Cell
|
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 myofibroblast populations.
|
[
{
"end": 132,
"label": "CellType",
"start": 112,
"text": "FRC-like fibroblasts"
},
{
"end": 213,
"label": "CellType",
"start": 188,
"text": "myofibroblast populations"
}
] |
Single_Cell
|
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.
|
[
{
"end": 115,
"label": "CellType",
"start": 92,
"text": "superficial fibroblasts"
},
{
"end": 155,
"label": "CellType",
"start": 135,
"text": "FRC-like fibroblasts"
}
] |
Single_Cell
|
Diseases with scarring risk were characterized by a uniquely high prevalence of F6: inflammatory myofibroblasts, which was not observed in low scarring risk or established fibrosis (Fig. 4b ).
|
[
{
"end": 111,
"label": "CellType",
"start": 84,
"text": "inflammatory myofibroblasts"
}
] |
Single_Cell
|
F7: myofibroblasts were observed at a similar prevalence in diseases with scarring risk and established fibrosis.
|
[
{
"end": 18,
"label": "CellType",
"start": 4,
"text": "myofibroblasts"
}
] |
Single_Cell
|
These data point toward F6: inflammatory myofibroblast as a population influencing scarring risk, but which are largely absent in established fibrosis.
|
[
{
"end": 54,
"label": "CellType",
"start": 28,
"text": "inflammatory myofibroblast"
}
] |
Single_Cell
|
F8: fascia-like myofibroblasts were also elevated in established fibrosis but were predominantly observed in Dupuytren contracture, a fibroproliferative disease of the palmar fascia (Fig. 4a ).
|
[
{
"end": 181,
"label": "Tissue",
"start": 168,
"text": "palmar fascia"
},
{
"end": 30,
"label": "CellType",
"start": 4,
"text": "fascia-like myofibroblasts"
}
] |
Single_Cell
|
We used two further approaches to demonstrate the role for distinct fibroblast subtypes predicting scarring risk.
|
[
{
"end": 87,
"label": "CellType",
"start": 68,
"text": "fibroblast subtypes"
}
] |
Single_Cell
|
First, we trained a random forest classifier and identified that F6: inflammatory myofibroblasts and F7: myofibroblasts were the most important fibroblast subtypes for predicting scarring risk category (Extended Data Fig. 6b ).
|
[
{
"end": 119,
"label": "CellType",
"start": 105,
"text": "myofibroblasts"
},
{
"end": 96,
"label": "CellType",
"start": 69,
"text": "inflammatory myofibroblasts"
},
{
"end": 163,
"label": "CellType",
"start": 144,
"text": "fibroblast subtypes"
}
] |
Single_Cell
|
Second, we profiled a well-recognized myofibroblast marker (LRRC15) at the protein level.
|
[] |
Single_Cell
|
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 ).
|
[
{
"end": 93,
"label": "Tissue",
"start": 55,
"text": "inflamed hidradenitis suppurativa skin"
},
{
"end": 122,
"label": "Tissue",
"start": 106,
"text": "noninflamed skin"
},
{
"end": 139,
"label": "Tissue",
"start": 126,
"text": "inflamed skin"
},
{
"end": 185,
"label": "Tissue",
"start": 163,
"text": "atopic dermatitis skin"
}
] |
Single_Cell
|
Having established that disease-associated fibroblasts are enriched in distinct scarring categories, we next used spatial transcriptomics to validate these fibroblast populations in distinct scarring risk stroma (Fig. 4d–f and Supplementary Fig. 3 ) .
|
[
{
"end": 54,
"label": "CellType",
"start": 24,
"text": "disease-associated fibroblasts"
},
{
"end": 178,
"label": "CellType",
"start": 156,
"text": "fibroblast populations"
},
{
"end": 211,
"label": "Tissue",
"start": 191,
"text": "scarring risk stroma"
}
] |
Single_Cell
|
In keeping with scRNA-seq data (Fig. 4a ), F3: FRC-like fibroblasts were expanded in inflamed atopic dermatitis skin (low risk), without major myofibroblasts (Fig. 4d,f and Extended Data Fig. 6c ).
|
[
{
"end": 67,
"label": "CellType",
"start": 47,
"text": "FRC-like fibroblasts"
},
{
"end": 116,
"label": "Tissue",
"start": 85,
"text": "inflamed atopic dermatitis skin"
},
{
"end": 157,
"label": "CellType",
"start": 143,
"text": "myofibroblasts"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 40,
"label": "CellType",
"start": 21,
"text": "FRC-like population"
},
{
"end": 85,
"label": "Tissue",
"start": 48,
"text": "superficial perivascular immune niche"
}
] |
Single_Cell
|
In melanoma (scarring risk), aside from F1, the entire stroma comprised F6: inflammatory myofibroblasts and F7: myofibroblasts (Fig. 4e,f and Extended Data Fig. 6g ).
|
[
{
"end": 61,
"label": "Tissue",
"start": 55,
"text": "stroma"
},
{
"end": 126,
"label": "CellType",
"start": 112,
"text": "myofibroblasts"
},
{
"end": 103,
"label": "CellType",
"start": 76,
"text": "inflammatory myofibroblasts"
}
] |
Single_Cell
|
F7: myofibroblasts showed a matrix-producing phenotype ( COL1A1 , COL3A1 and POSTN ) that characterizes myofibroblastic cancer-associated fibroblasts (CAFs) (myoCAFs) .
|
[
{
"end": 18,
"label": "CellType",
"start": 4,
"text": "myofibroblasts"
},
{
"end": 149,
"label": "CellType",
"start": 104,
"text": "myofibroblastic cancer-associated fibroblasts"
},
{
"end": 155,
"label": "CellType",
"start": 151,
"text": "CAFs"
},
{
"end": 165,
"label": "CellType",
"start": 158,
"text": "myoCAFs"
}
] |
Single_Cell
|
F6: inflammatory myofibroblasts 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 ).
|
[
{
"end": 31,
"label": "CellType",
"start": 4,
"text": "inflammatory myofibroblasts"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 154,
"label": "CellType",
"start": 116,
"text": "disease-associated fibroblast subtypes"
}
] |
Single_Cell
|
The F6: inflammatory myofibroblast signature score was highest in hidradenitis suppurativa, acne and keratinocytic skin cancers.
|
[] |
Single_Cell
|
Overall, our findings support distinct stromal composition in skin diseases associated with differential scarring risk.
|
[] |
Single_Cell
|
F6: inflammatory myofibroblasts 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: myofibroblasts.
|
[
{
"end": 243,
"label": "CellType",
"start": 229,
"text": "myofibroblasts"
},
{
"end": 31,
"label": "CellType",
"start": 4,
"text": "inflammatory myofibroblasts"
}
] |
Single_Cell
|
The differentiation process of healthy fibroblasts into myofibroblasts remains poorly understood in human tissues despite its clinical relevance.
|
[
{
"end": 70,
"label": "CellType",
"start": 56,
"text": "myofibroblasts"
},
{
"end": 50,
"label": "CellType",
"start": 31,
"text": "healthy fibroblasts"
},
{
"end": 113,
"label": "Tissue",
"start": 100,
"text": "human tissues"
}
] |
Single_Cell
|
Fibroblasts are tissue resident, and thus intermediate states of myofibroblast differentiation are likely to be captured in the molecular snapshots of skin diseases analyzed.
|
[
{
"end": 11,
"label": "CellType",
"start": 0,
"text": "Fibroblasts"
}
] |
Single_Cell
|
We therefore performed trajectory analysis of fibroblasts in diseased skin to gain further insights into myofibroblast differentiation, before utilizing time-resolved human wound data as a validation of dynamic changes in stromal composition.
|
[
{
"end": 57,
"label": "CellType",
"start": 46,
"text": "fibroblasts"
},
{
"end": 74,
"label": "Tissue",
"start": 61,
"text": "diseased skin"
}
] |
Single_Cell
|
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 ).
|
[
{
"end": 41,
"label": "CellType",
"start": 22,
"text": "fibroblast subtypes"
},
{
"end": 182,
"label": "CellType",
"start": 160,
"text": "fibroblast populations"
},
{
"end": 220,
"label": "Tissue",
"start": 208,
"text": "hair-bearing"
},
{
"end": 238,
"label": "Tissue",
"start": 225,
"text": "hairless skin"
}
] |
Single_Cell
|
F7: myofibroblasts were a terminally differentiated myofibroblast state (Fig. 5a–c ), consistent with their presence in established fibrosis.
|
[
{
"end": 18,
"label": "CellType",
"start": 4,
"text": "myofibroblasts"
},
{
"end": 71,
"label": "CellType",
"start": 26,
"text": "terminally differentiated myofibroblast state"
}
] |
Single_Cell
|
We observed two potential sources for F7: myofibroblasts in skin across analyses (Fig. 5b,c and Extended Data Fig. 7b ).
|
[
{
"end": 56,
"label": "CellType",
"start": 42,
"text": "myofibroblasts"
},
{
"end": 64,
"label": "Tissue",
"start": 60,
"text": "skin"
}
] |
Single_Cell
|
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