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Biomedicines
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Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis
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Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 19836

Special Issue Editor

Dr. Timo Gaber

E-Mail Website
Guest Editor
1. Department of Rheumatology and Clinical Immunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
2. German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, 10117 Berlin, Germany
Interests: cellular energy metabolism of immune cells; cellular glucocorticoid mechanisms and the role of HIF’s in cellular immune response and regeneration processes such as wound and fracture healing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fibroblasts are spindle-shaped, site-specific cells of mesenchymal origin in the interstitial spaces of organs and part of the connective tissue. They include synovial fibroblasts, dermal fibroblasts, and bone-marrow stromal cells. Fibroblasts are the primary source of interstitial extracellular matrix (ECM) proteins, mainly including collagen fibers, which, together with the proteoglycans that are also formed, provide increased strength for the extracellular matrix, forming a scaffold for cells. In addition to providing a scaffold for cells, ECM proteins play key roles in determining cell phenotype and function. Beside ECM proteins, fibroblasts secrete proteolytic enzymes, growth factors, cytokines and chemokines. Finally, fibroblasts adhere to and contract connective tissue and are capable of transdifferentiating into activated proliferative fibroblasts or myofibroblasts. Thus, it is not surprising that they are key players in acute and chronic inflammatory processes such as wound healing and fibrosis, cirrhosis dermatitis and arthritis. In physiological ECM maintenance, the fibroblast repair program is self-limiting. By contrast, pathological fibrosis is characterized by uncontrolled fibroblast activation that results in exaggerated and persistent ECM accumulation and remodeling. The responses of fibroblasts to activation include proliferation, fibrinogenesis, and the release of cytokine and proteolytic enzymes. Fibroblasts are critical components of the granulation tissue of healing wounds or broken bones during soft callus formation. In the healing wound, the number of fibroblasts increases, while the number of inflammatory cells decreases. Increased numbers of fibroblasts or myofibroblasts occur primarily due to the local proliferation of local fibroblasts or other cells of mesenchymal origin such as pericytes, liver perisinusoidal cells, kidney mesangial cells or epithelial cells after epithelial–mesenchymal transition. Myofibroblasts can also develop from circulating precursors such as mononuclear cells and circulating fibrocytes. Peripheral blood fibrocytes rapidly enter the site of injury at the same time as circulating inflammatory cells. Although important players in the process of wound healing, fibroblasts are involved in regulating many chronic inflammatory diseases such as rheumatoid arthritis, primary biliary cirrhosis, atherosclerosis, kidney interstitial fibrosis and peritoneal fibrosis. This Special Issue will focus on fibroblasts and their critical role in a variety of diseases. In particular, for this Special Issue, contributions dealing with the characterization of fibroblasts, their mechanistic and metabolic switcesh from tissue-resident fibroblasts to proliferative myofibroblasts, fibrometabolism, the homing of fibrocytes to sites of inflammation, model systems of fibrosis and therapeutic interference to prevent or treat fibrosis are highly encouraged.

Dr. Timo Gaber
Guest Editor

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Keywords

  • fibroblasts
  • myofibroblasts
  • fibrocytes
  • fibrosis
  • inflammation
  • tissue regeneration
  • wound healing
  • extracellular matrix
  • arthritis fibrometabolism
  • epithelial–mesenchymal transition

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Published Papers (6 papers)

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Research

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13 pages, 1493 KiB  
Article
Comparative Evaluation of Inducible Cre Mouse Models for Fibroblast Targeting in the Healthy and Infarcted Myocardium
by Laura Pilar Aguado-Alvaro, Nerea Garitano, Gloria Abizanda, Eduardo Larequi, Felipe Prosper and Beatriz Pelacho
Biomedicines 2022, 10(10), 2350; https://doi.org/10.3390/biomedicines10102350 - 21 Sep 2022
Cited by 3 | Viewed by 2702
Abstract
Several Cre recombinase transgenic mouse models have been generated for cardiac fibroblast (CF) tracking and heart regulation. However, there is still no consensus on the ideal mouse model to optimally identify and/or regulate these cells. Here, a comparative evaluation of the efficiency and [...] Read more.
Several Cre recombinase transgenic mouse models have been generated for cardiac fibroblast (CF) tracking and heart regulation. However, there is still no consensus on the ideal mouse model to optimally identify and/or regulate these cells. Here, a comparative evaluation of the efficiency and specificity of the indirect reporter Cre-loxP system was carried out in three of the most commonly used fibroblast reporter transgenic mice (Pdgfra-CreERT2, Col1a1-CreERT2 and PostnMCM) under healthy and ischemic conditions, to determine their suitability in in vivo studies of cardiac fibrosis. We demonstrate optimal Cre recombinase activity in CF (but also, although moderate, in endothelial cells (ECs)) derived from healthy and infarcted hearts in the PDGFRa-creERT2 mouse strain. In contrast, no positive reporter signal was found in CF derived from the Col1a1-CreERT2 mice. Finally, in the PostnMCM line, fluorescent reporter expression was specifically detected in activated CF but not in EC, which leads us to conclude that it may be the most reliable model for future studies on cardiovascular disease. Importantly, no lethality or cardiac fibrosis were induced after tamoxifen administration at the established doses, either in healthy or infarcted mice of the three fibroblast reporter lineages. This study lays the groundwork for future efficient in vivo CF tracking and functional analyses. Full article
(This article belongs to the Special Issue Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis)
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22 pages, 5432 KiB  
Article
Immediate Effects of Extracorporeal Shock Wave Therapy in Fascial Fibroblasts: An In Vitro Study
by Carmelo Pirri, Caterina Fede, Lucia Petrelli, Enrico De Rose, Carlo Biz, Diego Guidolin, Raffaele De Caro and Carla Stecco
Biomedicines 2022, 10(7), 1732; https://doi.org/10.3390/biomedicines10071732 - 18 Jul 2022
Cited by 7 | Viewed by 3082
Abstract
Extracorporeal shock waves (ESWs) are used in the treatment of soft tissue injuries, but their role in the treatment of myofascial pain has not yet been demonstrated. The aim of this study was to investigate changes in cell biology of fibroblasts derived from [...] Read more.
Extracorporeal shock waves (ESWs) are used in the treatment of soft tissue injuries, but their role in the treatment of myofascial pain has not yet been demonstrated. The aim of this study was to investigate changes in cell biology of fibroblasts derived from deep/muscular fascia following treatment with ESWs. Primary fascial fibroblasts were collected from small samples of human fascia lata of the thigh of three volunteer patients (two men, one woman) during orthopedic surgery, and put in culture. These cells were exposed to 100 impulses of 0.05 mJ/mm2 with a frequency of 2.5 Hz, using 3D-printed support. This study demonstrated for the first time that ESWs can lead to in vitro production of hyaluronan-rich vesicles immediately after the treatment. At 1, 4, and 24 h after treatment, Alcian blue and Toluidine blue staining; immunocytochemistry to detect hyaluronic acid binding protein (HABP), collagen I, and collagen III; and transmission electron microscopy demonstrated that these vesicles are rich in hyaluronan and collagen I and III. The diameter of these vesicles was assessed, highlighting a small size at 1 h after ESW treatment, whereas at 4 and 24 h, they had an increase in the size. Particularly evident was the release of hyaluronan-rich vesicles, collagen-I, and collagen-III starting at 1 h, with an increase at 4 h and maintenance by 24 h. These in vitro data indicate that fascial cells respond to ESW treatment by regulating and remodeling the formation of extracellular matrix. Full article
(This article belongs to the Special Issue Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis)
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21 pages, 4881 KiB  
Article
The Impact of Inflammatory Stimuli on Xylosyltransferase-I Regulation in Primary Human Dermal Fibroblasts
by Thanh-Diep Ly, Christopher Lindenkamp, Eva Kara, Vanessa Schmidt, Anika Kleine, Bastian Fischer, Doris Hendig, Cornelius Knabbe and Isabel Faust-Hinse
Biomedicines 2022, 10(6), 1451; https://doi.org/10.3390/biomedicines10061451 - 19 Jun 2022
Cited by 5 | Viewed by 2370
Abstract
Inflammation plays a vital role in regulating fibrotic processes. Beside their classical role in extracellular matrix synthesis and remodeling, fibroblasts act as immune sentinel cells participating in regulating immune responses. The human xylosyltransferase-I (XT-I) catalyzes the initial step in proteoglycan biosynthesis and was [...] Read more.
Inflammation plays a vital role in regulating fibrotic processes. Beside their classical role in extracellular matrix synthesis and remodeling, fibroblasts act as immune sentinel cells participating in regulating immune responses. The human xylosyltransferase-I (XT-I) catalyzes the initial step in proteoglycan biosynthesis and was shown to be upregulated in normal human dermal fibroblasts (NHDF) under fibrotic conditions. Regarding inflammation, the regulation of XT-I remains elusive. This study aims to investigate the effect of lipopolysaccharide (LPS), a prototypical pathogen-associated molecular pattern, and the damage-associated molecular pattern adenosine triphosphate (ATP) on the expression of XYLT1 and XT-I activity of NHDF. We used an in vitro cell culture model and mimicked the inflammatory tissue environment by exogenous LPS and ATP supplementation. Combining gene expression analyses, enzyme activity assays, and targeted gene silencing, we found a hitherto unknown mechanism involving the inflammasome pathway components cathepsin B (CTSB) and caspase-1 in XT-I regulation. The suppressive role of CTSB on the expression of XYLT1 was further validated by the quantification of CTSB expression in fibroblasts from patients with the inflammation-associated disease Pseudoxanthoma elasticum. Altogether, this study further improves the mechanistic understanding of inflammatory XT-I regulation and provides evidence for fibroblast-targeted therapies in inflammatory diseases. Full article
(This article belongs to the Special Issue Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis)
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20 pages, 2402 KiB  
Article
Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes
by Nina Yao, Theresa Tretter, Peter Kvacskay, Wolfgang Merkt, Norbert Blank, Hanns-Martin Lorenz and Lars-Oliver Tykocinski
Biomedicines 2021, 9(10), 1413; https://doi.org/10.3390/biomedicines9101413 - 8 Oct 2021
Cited by 2 | Viewed by 2760
Abstract
Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi [...] Read more.
Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi affect pro- and anti-inflammatory circuits in the bidirectional interplay between SF and immune cells. Here, we examined the effects of tofacitinib, baricitinib and upadacitinib on crosstalk between SF and T or B lymphocytes in vitro and compared them with those of biologic disease modifying anti-rheumatic drugs (bDMARDs). JAKi dose-dependently suppressed cytokine secretion of T helper (Th) cells and decreased interleukin (IL)-6 and matrix metalloproteinase (MMP)3 secretion of SF stimulated by Th cells. Importantly, JAK inhibition attenuated the enhanced memory response of chronically stimulated SF. Vice versa, JAKi reduced the indoleamine-2,3-dioxygenase (IDO)1-mediated suppression of T cell-proliferation by SF. Remarkably, certain bDMARDs were as efficient as JAKi in suppressing the IL-6 and MMP3 secretion of SF stimulated by Th (adalimumab, secukinumab) or B cells (canakinumab) and combining bDMARDs with JAKi had synergistic effects. In conclusion, JAKi limit pro-inflammatory circuits in the crosstalk between SF and lymphocytes; however, they also weaken the immunosuppressive functions of SF. Both effects were dose-dependent and may contribute to heterogeneity in clinical response to treatment. Full article
(This article belongs to the Special Issue Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis)
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21 pages, 3585 KiB  
Article
Vocal Fold Fibroblasts in Reinke’s Edema Show Alterations Involved in Extracellular Matrix Production, Cytokine Response and Cell Cycle Control
by Magdalena Grill, Isaac Lazzeri, Andrijana Kirsch, Nina Steurer, Tanja Grossmann, Michael Karbiener, Ellen Heitzer and Markus Gugatschka
Biomedicines 2021, 9(7), 735; https://doi.org/10.3390/biomedicines9070735 - 26 Jun 2021
Cited by 7 | Viewed by 2715
Abstract
The voice disorder Reinke’s edema (RE) is a smoking- and voice-abuse associated benign lesion of the vocal folds, defined by an edema of the Reinke’s space, accompanied by pathological microvasculature changes and immune cell infiltration. Vocal fold fibroblasts (VFF) are the main cell [...] Read more.
The voice disorder Reinke’s edema (RE) is a smoking- and voice-abuse associated benign lesion of the vocal folds, defined by an edema of the Reinke’s space, accompanied by pathological microvasculature changes and immune cell infiltration. Vocal fold fibroblasts (VFF) are the main cell type of the lamina propria and play a key role in the disease progression. Current therapy is restricted to symptomatic treatment. Hence, there is an urgent need for a better understanding of the molecular causes of the disease. In the present study, we investigated differential expression profiles of RE and control VFF by means of RNA sequencing. In addition, fast gene set enrichment analysis (FGSEA) was performed in order to obtain involved biological processes, mRNA and protein levels of targets of interest were further evaluated. We identified 74 differentially regulated genes in total, 19 of which were upregulated and 55 downregulated. Differential expression analysis and FGSEA revealed upregulated genes and pathways involved in extracellular matrix (ECM) remodeling, inflammation and fibrosis. Downregulated genes and pathways were involved in ECM degradation, cell cycle control and proliferation. The current study addressed for the first time a direct comparison of VFF from RE to control and evaluated immediate functional consequences. Full article
(This article belongs to the Special Issue Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis)
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Review

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14 pages, 898 KiB  
Review
Role and Function of Mesenchymal Stem Cells on Fibroblast in Cutaneous Wound Healing
by Kotaro Tanaka, Ryohei Ogino, Sho Yamakawa, Shota Suda and Kenji Hayashida
Biomedicines 2022, 10(6), 1391; https://doi.org/10.3390/biomedicines10061391 - 12 Jun 2022
Cited by 13 | Viewed by 4547
Abstract
Skin wounds often repair themselves completely over time; however, this is true only for healthy individuals. Although various studies are being conducted to improve wound-healing therapy outcomes, the mechanisms of wound healing and regeneration are not completely understood yet. In recent years, mesenchymal [...] Read more.
Skin wounds often repair themselves completely over time; however, this is true only for healthy individuals. Although various studies are being conducted to improve wound-healing therapy outcomes, the mechanisms of wound healing and regeneration are not completely understood yet. In recent years, mesenchymal stem cells (MSCs) have been reported to contribute significantly to wound healing and regeneration. Understanding the function of MSCs will help to elucidate the fundamentals of wound healing. MSCs are multipotent stem cells that are used in regenerative medicine for their ability to self-renew and differentiate into bone, fat, and cartilage, with few ethical problems associated with cell harvesting. Additionally, they have anti-inflammatory and immunomodulatory properties and antifibrotic effects via paracrine signaling, and many studies have been conducted to use them to treat graft-versus-host disease, inflammatory bowel disease, and intractable cutaneous wounds. Many substances derived from MSCs are involved in the wound-healing process, and specific cascades and pathways have been elucidated. This review aims to explain the fundamental role of MSCs in wound healing and the effects of MSCs on fibroblasts. Full article
(This article belongs to the Special Issue Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis)
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