In search for the ideal anatomical composition of vascularised human skin equivalents for systemic sclerosis translational research: should we recruit the telocytes?

Published on Sep 1, 2021in Annals of the Rheumatic Diseases16.102
· DOI :10.1136/ANNRHEUMDIS-2019-216371
Mirko Manetti32
Estimated H-index: 32
(UniFI: University of Florence),
Marco Matucci-Cerinic95
Estimated H-index: 95
(UniFI: University of Florence)
Sources
Abstract
The recent paper by Matei et al 1 has raised our interest on the feasibility and reliability of vascularised human skin equivalents for fibrosis research. This is a novel in vitro model which may replicate key features of fibrotic skin and may become a valuable platform for preclinical testing of innovative therapeutic strategies for systemic sclerosis (SSc) and other cutaneous fibrosing conditions. In this informative study, an engineered human skin equivalent featuring a functional vascular system with physiological perfusion was established by sequential seeding of primary human endothelial cells, fibroblasts and keratinocytes on a three-dimensional (3D) extracellular matrix scaffold.1 Elegantly, the authors have shown that their 3D system may reproduce the main features of human skin relevant for the pathogenesis of skin fibrosis. Indeed, the exposure of these vascularised human skin equivalents to profibrotic transforming growth factor-β (TGFβ) has induced the fibroblast-to-myofibroblast transition and abnormal deposition of extracellular matrix, thus closely mimicking the SSc skin microenvironment.1 Moreover, the induction of dermal fibrosis was efficiently prevented by nintedanib, a tyrosine kinase inhibitor with proven antifibrotic effects, which further demonstrated that this model might serve as a suitable test system for future targeted therapies. The authors have also clearly discussed how their innovative model may help in overcoming …
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#1A. E. Matei (FAU: University of Erlangen-Nuremberg)H-Index: 4
#2Chih-Wei Chen (FAU: University of Erlangen-Nuremberg)H-Index: 13
Last. Jörg H W Distler (FAU: University of Erlangen-Nuremberg)H-Index: 87
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Objectives Fibrosis is a complex pathophysiological process involving interplay between multiple cell types. Experimental modelling of fibrosis is essential for the understanding of its pathogenesis and for testing of putative antifibrotic drugs. However, most current models employ either phylogenetically distant species or rely on human cells cultured in an artificial environment. Here we evaluated the potential of vascularised in vitro human skin equivalents as a novel model of skin fibrosis a...
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#1Sara M. Garrett (MUSC: Medical University of South Carolina)H-Index: 7
#2DeAnna Baker Frost (MUSC: Medical University of South Carolina)H-Index: 4
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Fibroblasts are the effector cells of fibrosis characteristic of systemic sclerosis (SSc, scleroderma) and other fibrosing conditions. The excess production of extracellular matrix (ECM) proteins i...
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#1Lidia Ibba-Manneschi (UniFI: University of Florence)H-Index: 30
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Telocytes are a peculiar stromal (interstitial) cell type implicated in tissue homeostasis and development, as well as in the pathophysiology of several disorders. Severe damage and reduction of telocytes have been reported during fibrotic remodeling of multiple organs in various diseases, including scleroderma, Crohn’s disease, ulcerative colitis, and liver fibrosis, as well as in chronic inflammatory lesions like those of primary Sjogren’s syndrome and psoriasis. Owing to their close relations...
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#1Yuli Kang (Fudan University)H-Index: 1
#2Zaihua Zhu (Fudan University)H-Index: 1
Last. Qiangqiang Zhang (Fudan University)H-Index: 1
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It is already accepted that telocytes (TCs) represent a new type of interstitial cells in human dermis. In normal skin, TCs have particular spatial relations with different dermal structures such as blood vessels, hair follicles, arrector pili muscles or segments of sebaceous and/or eccrine sweat glands. The distribution and the density of TCs is affected in various skin pathological conditions. Previous studies mentioned the particular (ultra)structure of TCs and also their immunophenotype, miR...
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Systemic sclerosis, an autoimmune disease of unknown origin, is characterized by progressive fibrosis that can affect all organs of the body. To date, there are no effective therapies for the disease. This paucity of treatment options is primarily because of limited understanding of the processes that initiate and promote fibrosis in general and a lack of animal models that specifically emulate the chronic nature of systemic sclerosis. Most models capitulate acute injury-induced fibrosis in spec...
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#1Ryan R. Driskell ('KCL': King's College London)H-Index: 23
#2Fiona M. Watt ('KCL': King's College London)H-Index: 124
Fibroblasts are found in most tissues, yet they remain poorly characterised. Different fibroblast subpopulations with distinct functions have been identified in the skin. This functional heterogeneity reflects the varied fibroblast lineages that arise from a common embryonic precursor. In addition to autocrine signals, fibroblasts are highly responsive to Wnt-regulated signals from the overlying epidermis, which can act both locally, via extracellular matrix (ECM) deposition, and via secreted fa...
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Systemic sclerosis (SSc) is a complex connective tissue disease characterized by fibrosis of the skin and various internal organs. In SSc, telocytes, a peculiar type of stromal (interstitial) cells, display severe ultrastructural damages and are progressively lost from the clinically affected skin. The aim of the present work was to investigate the presence and distribution of telocytes in the internal organs of SSc patients. Archival paraffin-embedded samples of gastric wall, myocardium and lun...
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Telocytes, a peculiar type of stromal cells, have been recently identified in a variety of tissues and organs, including human skin. Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease characterized by fibrosis of the skin and internal organs. We presently investigated telocyte distribution and features in the skin of SSc patients compared with normal skin. By an integrated immunohistochemical and transmission electron microscopy approach, we confirmed that telocytes wer...
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#1Thomas Hügle (Newcastle University)H-Index: 25
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Objective To describe the cellular source of transforming growth factor β (TGFβ) in the dermis of patients with systemic sclerosis (SSc). Methods We performed electron microscopy (EM) with immunogold labeling on skin biopsy specimens from 7 patients with SSc and 3 healthy control subjects. For TGFβ quantification, the numbers of gold particles per square micron were calculated. The origin of mast cells was confirmed and quantified by toluidine blue staining and light microscopy. Degranulation wa...
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Cited By2
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#1A. E. Matei (FAU: University of Erlangen-Nuremberg)H-Index: 4
#2Jörg H W Distler (FAU: University of Erlangen-Nuremberg)H-Index: 87
We would like to thank Dr Manetti and Prof Matucci-Cerinic1 for their stimulating letter on our manuscript.2 The authors discuss strengths and potential limitations of vascularised skin equivalents as a novel in vitro model for systemic sclerosis (SSc). They raise two key points: 1. Although the model includes key populations of cells relevant to skin homeostasis and to the pathogenesis of SSc such as fibroblasts, endothelial cells and keratinocytes, other relevant cell populations are not inclu...
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#1Eloisa Romano (UniFI: University of Florence)H-Index: 19
#2Irene Rosa (UniFI: University of Florence)H-Index: 18
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Telocytes (TCs), commonly referred to as TCs/CD34+ stromal cells, are a peculiar type of interstitial cells with distinctive morphologic traits that are supposed to exert several biological functions, including tissue homeostasis regulation, cell-to-cell signaling, immune surveillance, and reparative/regenerative effects. At present, the majority of studies investigating these cells are mainly descriptive and focus only on their morphology, with a consequent paucity of functional data. To gain r...
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