Poised cell circuits in human skin are activated in disease

Reynolds, Gary; Végh, Péter; Fletcher, James; Ef, Poyner; Stephenson, Emily; I, Goh; Ra, Botting; Huang, Ni; Olabi, Bayanne; Dubois, Anna; Dixon, David; Green, K; Maunder, Daniel; Engelbert, Justin; Efremova, Mirjana; Polański, Krzysztof; Jardine, Laura; Jones, Claire; Neß, Thomas; Horsfall, Dave; McGrath, Jim; Carey, Christopher D.; Popescu, Dorin-Mirel; Webb, Simone; Wang, X; Sayer, Ben; Park, J; Va, Negri; Belokhvostova, Daria; Lynch, Magnus; McDonald, David; Filby, Andrew; Hagai, Tzachi; Meyer, KB; Husain, Akhtar; Coxhead, Jonathan; Vento‐Tormo, Roser; Behjati, Sam; Lisgo, SN; Villani, Alexandra Chloé; Bacardit, Jaume; Jones, Philip H.; O'Toole, EA; Ogg, Graham S.; Rajan, Neil; Nj, Reynolds; Sa, Teichmann; Watt, Fiona M.; Haniffa, Muzlifah

doi:10.1101/2020.11.05.369363

Cited by 9 publications

(11 citation statements)

References 105 publications

(133 reference statements)

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“…So far single cell RNA sequencing of cells from adult human skin has identified one pericyte population, which expresses RGS5 and ACTA2 (Philippeos et al, 2018;Vorstandlechner et al, 2020). However, a second pericyte population has been identified in skin from patients with atopic dermatitis and psoriasis; these pericytes have a proposed role in leukocyte recruitment and TNFα-mediated signaling (Reynolds et al, 2020(Reynolds et al, , 2021.…”

Section: Discussionmentioning

confidence: 99%

Distinct Fibroblast Lineages Give Rise to NG2+ Pericyte Populations in Mouse Skin Development and Repair

Goss

Rognoni

Salameti

et al. 2021

Front. Cell Dev. Biol.

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We have examined the developmental origins of Ng2+ perivascular cell populations that adhere to the basement membrane of blood vessels, and their contribution to wound healing. Neural/glial antigen 2 (Ng2) labeled most perivascular cells (70–80%) in developing and adult mouse back skin, a higher proportion than expressed by other pericyte markers Tbx18, Nestin and Pdgfrβ. In adult mouse back skin Ng2+ perivascular cells could be categorized into 4 populations based on whether they expressed Pdgfrα and Pdgfrβ individually or in combination or were Pdgfr-negative. Lineage tracing demonstrated that although Ng2+ cells in embryonic and neonatal back skin contributed to multiple cell types they did not give rise to interfollicular fibroblasts within the dermis. Lineage tracing of distinct fibroblast populations during skin development showed that papillary fibroblasts (Lrig1+) gave rise to Ng2+ perivascular cells in the upper dermis, whilst Ng2+ perivascular cells in the lower dermis were primarily derived from reticular Dlk1+ fibroblasts. Following wounding of adult skin, Ng2+ dermal cells only give rise to Ng2+ blood vessel associated cells and did not contribute to other fibroblast lineages. The relative abundance of Ng2+ Pdgfrβ+ perivascular populations was comparable in wounded and non-wounded skin, indicating that perivascular heterogeneity was maintained during full thickness skin repair. In the wound bed Ng2+ perivascular populations were primarily derived from Lrig1+ papillary or Dlk1+ reticular fibroblast lineages, according to the location of the regenerating blood vessels. We conclude that Ng2+ perivascular cells represent a heterogeneous lineage restricted population that is primarily recruited from the papillary or reticular fibroblast lineages during tissue regeneration.

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Section: Discussionmentioning

confidence: 99%

Distinct Fibroblast Lineages Give Rise to NG2+ Pericyte Populations in Mouse Skin Development and Repair

Goss

Rognoni

Salameti

et al. 2021

Front. Cell Dev. Biol.

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“…To circumvent the dilution of low-abundant, but important transcripts, single-cell RNAseq (scRNA-seq) can be applied. scRNA-seq of a small number of psoriatic samples have identified the important role of endothelial cells expressing leukocyte adhesion molecules 44 as well as trajectories for keratinocyte differentiation 45 .…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing of a large number of psoriatic patients identifies 131 novel miRNAs and 11 miRNAs associated with disease severity

Solvin

Chawla

Olsen

et al. 2021

Preprint

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BackgroundMicroRNAs are small regulatory molecules that are dysregulated in psoriasis. Despite previous efforts, much is unknown about the regulatory mechanisms of psoriasis genetics and their contributions to disease development and activity.ObjectivesTo globally characterize the miRNAome of psoriatic skin in a large sample of psoriatic cases and controls for increased understanding of psoriasis pathophysiology.MethodsSkin biopsies from psoriatic cases (n=75) and non-psoriatic controls (n=57) were RNA sequenced. Count data was meta-analyzed with a previously published dataset (cases, n=24, controls, n=20), increasing the number of psoriatic cases four-fold from previously published studies. Differential expression analyses were performed comparing lesional psoriatic (PP), non-lesional psoriatic (PN) and control (NN) skin. Further, functional enrichment and cell specific analyses were performed.ResultsWe identified 439 significantly differentially expressed miRNAs (DEMs), of which 131 were novel and 11 were related to disease severity. Meta-analyses identified 20 DEMs between PN and NN, suggesting an inherent change in all psoriatic skin. By integrating the miRNA transcriptome with mRNA target interactions, we identified several functionally enriched terms, including ‘thyroid hormone signaling’, ‘insulin resistance’ and various infectious diseases. Cell specific expression analyses revealed that the upregulated DEMs were enriched in epithelial and immune cells.ConclusionsWe have provided the most comprehensive overview of the miRNome in psoriatic skin to date and identified a miRNA signature related to psoriasis severity. Our results may represent molecular links between psoriasis and related comorbidities and have outlined potential directions for future functional studies to identify biomarkers and treatment targets.

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“…For instance, it is yet to be demonstrated whether human synovial fibroblasts from RA patients release NGF – and whether they continue to do so in the many individuals who continue to experience pain in the absence of synovitis (53). We also know nothing about whether known fibroblast sub-populations in joint (22), skin (54) or other tissues (55) differentially affect nociceptor sensitization. Finally, we lack information on how fibroblasts contribute to the immune cell dysfunction frequently demonstrated and characterized in chronic pain states (10).…”

Section: Discussionmentioning

confidence: 99%

Fibroblasts – the neglected cell type in peripheral sensitization and chronic pain? - A systematic view on the current state of the literature

Shinotsuka

Denk

2021

Preprint

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Chronic pain and its underlying biological mechanisms have been studied for many decades, with a myriad of molecules, receptors and cell types known to contribute to abnormal pain sensations. We now know that besides an obvious role for neuronal populations in the peripheral and central nervous system, immune cells like microglia, macrophages and T cells are also important drivers of persistent pain. While neuroinflammation has therefore been widely studied in pain research, there is one cell-type that appears to be rather neglected in this context: the humble fibroblast. Fibroblasts may seem unassuming, but actually play a major part in regulating immune cell function and driving chronic inflammation. What is known about them in the context chronic pain? Here we set out to analyze the literature on this topic, using systematic screening and data extraction methods to obtain a balanced view on what has been published. We found that there has been surprisingly little research in this area: 134 articles met our inclusion criteria, only a tiny minority of which directly investigated interactions between fibroblasts and peripheral neurons. We categorized the articles we included, stratifying them according to what was investigated, the estimated quality of results, and any common conclusions. Fibroblasts are a ubiquitous cell type and a prominent source of many pro-algesic mediators in a wide variety of tissues. We think that they deserve a more central role in pain research and propose a new, testable model of how fibroblasts might drive peripheral neuron sensitization.

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Poised cell circuits in human skin are activated in disease

Cited by 9 publications

References 105 publications

Distinct Fibroblast Lineages Give Rise to NG2+ Pericyte Populations in Mouse Skin Development and Repair

Distinct Fibroblast Lineages Give Rise to NG2+ Pericyte Populations in Mouse Skin Development and Repair

RNA sequencing of a large number of psoriatic patients identifies 131 novel miRNAs and 11 miRNAs associated with disease severity

Fibroblasts – the neglected cell type in peripheral sensitization and chronic pain? - A systematic view on the current state of the literature

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