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The Role of Epithelial Cells in Scleroderma
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The Role of Epithelial Cells in Scleroderma

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Tissues and Organs".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 14900

Special Issue Editor

Dr. Richard Stratton

E-Mail Website
Guest Editor
Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital, UCL Division of Medicine, London NW32QG, UK
Interests: understanding inflammatory fibrosis in order to develop new treatments
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Systemic sclerosis (SSc, scleroderma) is a severe connective tissue disease initiated by environmental factors as well as by dysregulated immunity. The epithelial layers of the skin and affected internal organs may play an important role in the pathogenesis, since they are the first site of exposure to factors from the environment and are also highly endowed with antigen-presenting cells and effector T cell populations. Moreover, activated epithelial cells, such as those overlying wounds, are known to actively promote underlying fibroblasts leading to tissue repair. Intriguingly, we and others have found the scleroderma epidermis to have an activation state resembling the keratinocyte layer overlying wounds and have shown in co-culture experiments that the scleroderma epidermis promotes fibroblast activation leading to a pro-fibrotic response. Whilst full epithelial to mesenchyme transition (EMT) was not seen, a partially evoked form can be detected in which keratinocytes are losing epithelial markers and gaining certain fibroblast proteins. The results are aligned with other forms of fibrosis, where epithelial cell-fibroblast cross talk has been shown to have a role, but full EMT is not seen. The importance of these mechanisms in promoting the skin changes in scleroderma, and the more general involvement of epithelial cells in promoting lung and gut manifestations requires further investigation. Application of specific therapies targeting the epithelial-fibroblast crosstalk in clinical trials might give the most valuable insight overall.

Dr. Richard Stratton
Guest Editor

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Keywords

  • Fibrosis
  • Epithelial–fibroblast interaction
  • EMT
  • Cytokeratin 6 and 16

Published Papers (6 papers)

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Research

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11 pages, 1802 KiB  
Article
Autoantibodies Which Bind to and Activate Keratinocytes in Systemic Sclerosis
by Carine Moezinia, Valerie Wong, James Watson, Lydia Nagib, Sandra Lopez Garces, Siyu Zhang, Bahja Ahmed Abdi, Florence Newton, David Abraham and Richard Stratton
Cells 2023, 12(20), 2490; https://doi.org/10.3390/cells12202490 - 20 Oct 2023
Viewed by 1242
Abstract
Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised by pathological processes involving autoimmunity, vasculopathy and resultant extensive skin and organ fibrosis. Recent studies have demonstrated activation and aberrant wound healing responses in the epithelial layer of the skin in this disease, [...] Read more.
Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised by pathological processes involving autoimmunity, vasculopathy and resultant extensive skin and organ fibrosis. Recent studies have demonstrated activation and aberrant wound healing responses in the epithelial layer of the skin in this disease, implicating the epithelial keratinocytes as a source of pro-fibrotic and inflammatory mediators. In this paper, we investigated the role of Immunoglobulin G (IgG) autoantibodies directed against epithelial cells, as potential initiators and propagators of pathological keratocyte activation and the ensuing SSc fibrotic cascade. A keratinocyte cell-based ELISA is used to evaluate the binding of SSc IgG. SSc skin biopsies were stained by immunofluorescence for the presence of IgG in the keratinocyte layer. Moreover, IgG purified from SSc sera was evaluated for the potential to activate keratinocytes in tissue culture and to induce TLR2 and 3 signalling in reporter cell lines. We demonstrate enhanced binding of SSc IgG to keratinocytes and the activation of these cells leading to the release of IL-1α, representing a potential initiating pathway in this disease. Full article
(This article belongs to the Special Issue The Role of Epithelial Cells in Scleroderma)
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19 pages, 4753 KiB  
Article
Lymphatic Endothelial-to-Myofibroblast Transition: A Potential New Mechanism Underlying Skin Fibrosis in Systemic Sclerosis
by Irene Rosa, Eloisa Romano, Bianca Saveria Fioretto, Khadija El Aoufy, Silvia Bellando-Randone, Marco Matucci-Cerinic and Mirko Manetti
Cells 2023, 12(17), 2195; https://doi.org/10.3390/cells12172195 - 1 Sep 2023
Cited by 4 | Viewed by 1301
Abstract
At present, only a few reports have addressed the possible contribution of the lymphatic vascular system to the pathogenesis of systemic sclerosis (SSc). Based on the evidence that blood vascular endothelial cells can undertake the endothelial-to-myofibroblast transition (EndMT) contributing to SSc-related skin fibrosis, [...] Read more.
At present, only a few reports have addressed the possible contribution of the lymphatic vascular system to the pathogenesis of systemic sclerosis (SSc). Based on the evidence that blood vascular endothelial cells can undertake the endothelial-to-myofibroblast transition (EndMT) contributing to SSc-related skin fibrosis, we herein investigated whether the lymphatic endothelium might represent an additional source of profibrotic myofibroblasts through a lymphatic EndMT (Ly-EndMT) process. Skin sections from patients with SSc and healthy donors were immunostained for the lymphatic endothelial cell-specific marker lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) in combination with α-smooth muscle actin (α-SMA) as the main marker of myofibroblasts. Commercial human adult dermal lymphatic microvascular endothelial cells (HdLy-MVECs) were challenged with recombinant human transforming growth factor-β1 (TGFβ1) or serum from SSc patients and healthy donors. The expression of lymphatic endothelial cell/myofibroblast markers was measured by quantitative real-time PCR, Western blotting and immunofluorescence. Collagen gel contraction assay was performed to assess myofibroblast-like cell contractile ability. Lymphatic endothelial cells in intermediate stages of the Ly-EndMT process (i.e., coexpressing LYVE-1 and α-SMA) were found exclusively in the fibrotic skin of SSc patients. The culturing of HdLy-MVECs with SSc serum or profibrotic TGFβ1 led to the acquisition of a myofibroblast-like morphofunctional phenotype, as well as the downregulation of lymphatic endothelial cell-specific markers and the parallel upregulation of myofibroblast markers. In SSc, the Ly-EndMT might represent a previously overlooked pathogenetic process bridging peripheral microlymphatic dysfunction and skin fibrosis development. Full article
(This article belongs to the Special Issue The Role of Epithelial Cells in Scleroderma)
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23 pages, 7647 KiB  
Article
Single-Cell Analysis of ADSC Interactions with Fibroblasts and Endothelial Cells in Scleroderma Skin
by Marvin L. Frommer, Benjamin J. Langridge, Laura Awad, Sara Jasionowska, Christopher P. Denton, David J. Abraham, Jeries Abu-Hanna and Peter E. M. Butler
Cells 2023, 12(13), 1784; https://doi.org/10.3390/cells12131784 - 5 Jul 2023
Cited by 2 | Viewed by 2641
Abstract
Adipose-derived stem cells (ADSCs) as part of autologous fat grafting have anti-fibrotic and anti-inflammatory effects, but the exact mechanisms of action remain unknown. By simulating the interaction of ADSCs with fibroblasts and endothelial cells (EC) from scleroderma (SSc) skin in silico, we aim [...] Read more.
Adipose-derived stem cells (ADSCs) as part of autologous fat grafting have anti-fibrotic and anti-inflammatory effects, but the exact mechanisms of action remain unknown. By simulating the interaction of ADSCs with fibroblasts and endothelial cells (EC) from scleroderma (SSc) skin in silico, we aim to unravel these mechanisms. Publicly available single-cell RNA sequencing data from the stromal vascular fraction of 3 lean patients and biopsies from the skin of 10 control and 12 patients with SSc were obtained from the GEO and analysed using R and Seurat. Differentially expressed genes were used to compare the fibroblast and EC transcriptome between controls and SSc. GO and KEGG functional enrichment was performed. Ligand–receptor interactions of ADSCs with fibroblasts and ECs were explored with LIANA. Pro-inflammatory and extracellular matrix (ECM) interacting fibroblasts were identified in SSc. Arterial, capillary, venous and lymphatic ECs showed a pro-fibrotic and pro-inflammatory transcriptome. Most interactions with both cell types were based on ECM proteins. Differential interactions identified included NTN1, VEGFD, MMP2, FGF2, and FNDC5. The ADSC secretome may disrupt vascular and perivascular inflammation hubs in scleroderma by promoting angiogenesis and especially lymphangiogenesis. Key phenomena observed after fat grafting remain unexplained, including modulation of fibroblast behaviour. Full article
(This article belongs to the Special Issue The Role of Epithelial Cells in Scleroderma)
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15 pages, 8154 KiB  
Article
A Novel CD206 Targeting Peptide Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice
by Anghesom Ghebremedhin, Ahmad Bin Salam, Benjamin Adu-Addai, Steve Noonan, Richard Stratton, Md Shakir Uddin Ahmed, Chandra Khantwal, George R. Martin, Huixian Lin, Chris Andrews, Balasubramanyam Karanam, Udo Rudloff, Henry Lopez, Jesse Jaynes and Clayton Yates
Cells 2023, 12(9), 1254; https://doi.org/10.3390/cells12091254 - 26 Apr 2023
Cited by 13 | Viewed by 2805
Abstract
Activated M2-polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios, including Idiopathic Pulmonary Fibrosis (IPF). In this study, we investigated the effects of targeting the CD206 receptor in M2-like macrophages with a novel synthetic analogue of a naturally occurring Host Defense [...] Read more.
Activated M2-polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios, including Idiopathic Pulmonary Fibrosis (IPF). In this study, we investigated the effects of targeting the CD206 receptor in M2-like macrophages with a novel synthetic analogue of a naturally occurring Host Defense Peptide (HDP), RP-832c, to decrease profibrotic cytokines. RP-832c selectively binds to CD206 on M2-polarized bone marrow-derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression and a transient increase in M1-macrophage marker TNF-α. To elucidate the antifibrotic effects of RP-832c, we used a murine model of bleomycin (BLM)-induced early-stage pulmonary fibrosis. RP-832c significantly reduced fibrosis in a dose-dependent manner, and decreased CD206, TGF-β1, and α-SMA expression in mouse lungs. Similarly, in an established model of lung fibrosis, RP-832c significantly decreased lung fibrosis and significantly decreased inflammatory cytokines TNF-α, IL-6, IL-10, IFN-γ, CXCL1/2, and fibrosis markers TGF-β1 and MMP-13. In comparison with the FDA-approved drugs Nintedanib and Pirfenidone, RP-832c exhibited a similar reduction in fibrosis compared to Pirfenidone, and to a greater extent than Nintedanib, with no apparent toxicities observed. In summary, our findings showed that inhibiting the profibrotic alternatively activated M2-like macrophages using a novel peptide, RP-832c, could reduce BLM-induced pulmonary fibrosis in mice, warranting the therapeutic potential of this peptide for patients with pulmonary fibrosis. Full article
(This article belongs to the Special Issue The Role of Epithelial Cells in Scleroderma)
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10 pages, 4123 KiB  
Article
The Cell-Permeable Derivative of the Immunoregulatory Metabolite Itaconate, 4-Octyl Itaconate, Is Anti-Fibrotic in Systemic Sclerosis
by John Henderson, Sharadha Dayalan Naidu, Albena T. Dinkova-Kostova, Stefan Przyborski, Richard Stratton and Steven O′Reilly
Cells 2021, 10(8), 2053; https://doi.org/10.3390/cells10082053 - 10 Aug 2021
Cited by 14 | Viewed by 3447
Abstract
Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to skin fibrosis. Altered metabolism has recently been described in autoimmune diseases and SSc. Itaconate is a product of the Krebs cycle intermediate cis-aconitate and is an immunomodulator. This work examines [...] Read more.
Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to skin fibrosis. Altered metabolism has recently been described in autoimmune diseases and SSc. Itaconate is a product of the Krebs cycle intermediate cis-aconitate and is an immunomodulator. This work examines the role of the cell-permeable derivative of itaconate, 4-octyl itaconate (4-OI), in SSc. SSc and healthy dermal fibroblasts were exposed to 4-OI. The levels of collagen Nrf2-target genes and pro-inflammatory cytokines interleukin 6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) were determined. Levels of reactive oxygen species (ROS) as well as the gene expression of collagen and Cellular Communication Network Factor 2 (CCN2) were measured after transforming growth factor beta 1 (TGF-β1) stimulation in the presence or absence of 4-OI. Wild-type or Nrf2-knockout (Nrf2-KO) mouse embryonic fibroblasts (MEFs) were also treated with 4-OI to determine the role of Nrf2 in 4-OI-mediated effects. 4-OI reduced the levels of collagen in SSc dermal fibroblasts. Incubation with 4-OI led to activation of Nrf2 and its target genes heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). 4-OI activated antioxidant response element (ARE)-dependent gene expression, reduced inflammatory cytokine release and reduced TGF-β1-induced collagen and ROS production in dermal fibroblasts. The effects of 4-OI are dependent on Nrf2. The cell-permeable derivative of itaconate 4-OI is anti-fibrotic through upregulation of Nrf2 and could be a potential therapeutic option in an intractable disease. Full article
(This article belongs to the Special Issue The Role of Epithelial Cells in Scleroderma)
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Review

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14 pages, 747 KiB  
Review
Hiding in Plain Sight: Human Gingival Fibroblasts as an Essential, Yet Overlooked, Tool in Regenerative Medicine
by Asmaa Fadl and Andrew Leask
Cells 2023, 12(16), 2021; https://doi.org/10.3390/cells12162021 - 8 Aug 2023
Cited by 4 | Viewed by 2386
Abstract
Adult human gingival fibroblasts (HGFs), the most abundant cells in the oral cavity, are essential for maintaining oral homeostasis. Compared with other tissues, adult oral mucosal wounds heal regeneratively, without scarring. Relative to fibroblasts from other locations, HGFs are relatively refractory to myofibroblast [...] Read more.
Adult human gingival fibroblasts (HGFs), the most abundant cells in the oral cavity, are essential for maintaining oral homeostasis. Compared with other tissues, adult oral mucosal wounds heal regeneratively, without scarring. Relative to fibroblasts from other locations, HGFs are relatively refractory to myofibroblast differentiation, immunomodulatory, highly regenerative, readily obtained via minimally invasive procedures, easily and rapidly expanded in vitro, and highly responsive to growth factors and cytokines. Consequently, HGFs might be a superior, yet perhaps underappreciated, source of adult mesenchymal progenitor cells to use in tissue engineering and regeneration applications, including the treatment of fibrotic auto-immune connective tissue diseases such as scleroderma. Herein, we highlight in vitro and translational studies that have investigated the regenerative and differentiation potential of HGFs, with the objective of outlining current limitations and inspiring future research that could facilitate translating the regenerative potential of HGFs into the clinic. Full article
(This article belongs to the Special Issue The Role of Epithelial Cells in Scleroderma)
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