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Fibroblasts in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 21572

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Prof. Dr. Debby Laukens

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Department of Internal Medicine and Pediatrics, Faculty of Medicine, Ghent University, C. Heymanslaan 10, B-9000 Gent, Belgium
Interests: molecular biology; molecular genetics; mucosal immunology; host-bacteria interaction; inflammatory bowel diseases; gut fibrosis; gut-brain communication

Special Issue Information

Dear Colleagues,

Tissue fibrosis is estimated to contribute to nearly 45% of all deaths in the industrialized world. Noteworthy, the SARS-CoV-2 virus that is currently causing the COVID-19 pandemic leads to potentially persisting pulmonary fibrosis, and whether this will become progressive and create lung damage in these patients requires consideration. The key regulator cells that go awry during tissue fibrosis are the fibroblasts, exhibiting a variety of functions in the maintenance of tissue homeostasis and during wound healing. Of note, fibroblasts are also a highly abundant cell type in many tumors, actively influencing tumor growth and cancer progression.

A uniform function of fibroblasts across tissues is the production of extracellular matrix (ECM) components and ECM-modifying enzymes, which collectively constitutes the framework of the connective tissue. In addition, quiescent fibroblasts seem to respond to similar injury-induced signals that causes their differentiation into wound healing myofibroblast, irrespective of the tissue in which they reside. Aside from their role in connective tissue formation and wound healing, fibroblasts create a niche for tissue-resident stem cells, and contribute to immune regulation by secreting cytokines and anti-microbial peptides.

Next to the unifying functions of what we consider the typical fibroblast, we are increasingly recognizing their more specialized functions, and driven by technical advances in single cell phenotyping, fibroblast heterogeneity is increasingly being mapped. Most discriminating features between fibroblasts of different origin are dominated by ECM components, reflecting the differential tensile properties and water content of tissues and organs. However, also within a tissue, fibroblasts adopt different subphenotypes that fulfill specialized spatial roles.

Upon chronic injury or sustained/remitting-relapsing inflammation, myofibroblasts enforce tissue destruction by continuously producing excessive and disorganized ECM, which leads to stiffening of the matrix and the development of scar tissue. The stiffened matrix itself induces biomechanical cues in fibroblasts, which further stimulates pro-fibrotic pathways. Following their activation, fibroblasts return to a quiescent state or go in senescence or apoptosis, which are features that are often lost in fibrotic tissue and in tumors. Nonetheless, the presence of such plasticity creates hope for discovering therapeutic targets aiming to restore a tissue’s architecture or to limit tumor growth.

Fibroblasts are notoriously ‘enjoyable’ to study as they show remarkable independence for growing in a culture dish. They are undeniably intriguing cells that play crucial roles during health and disease, yet much remains to be uncovered with respect to their overall biology, functional heterogeneity and plasticity. We have launched a Special Issue of IJMS entitled “Fibroblasts in health and disease”, inviting you to contribute a research paper or review article for peer-review and potential publication. We would like to encourage you to submit articles focused on original human or animal experimental research in which fibroblast biology is central.

Prof. Dr. Debby Laukens
Guest Editor

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Keywords

fibrosis
fibroblast
mesenchymal cells
cancer-associated fibroblast
fibrotic disease
connective tissue
extracellular matrix
mechanotransduction

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Published Papers (7 papers)

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Research

11 pages, 1790 KiB

Open AccessArticle

CD36⁺ Fibroblasts Secrete Protein Ligands That Growth-Suppress Triple-Negative Breast Cancer Cells While Elevating Adipogenic Markers for a Model of Cancer-Associated Fibroblast

by Kosar Jabbari, Qingsu Cheng, Garrett Winkelmaier, Saori Furuta and Bahram Parvin

Int. J. Mol. Sci. 2022, 23(21), 12744; https://doi.org/10.3390/ijms232112744 - 22 Oct 2022

Cited by 5 | Viewed by 2900

Abstract

Tumor and stroma coevolve to facilitate tumor growth. Hence, effective tumor therapeutics would not only induce growth suppression of tumor cells but also revert pro-tumor stroma into anti-tumoral type. Previously, we showed that coculturing triple-negative or luminal A breast cancer cells with CD36⁺ fibroblasts (FBs) in a three-dimensional extracellular matrix induced their growth suppression or phenotypic reversion, respectively. Then, we identified SLIT3, FBLN-1, and PENK as active protein ligands secreted from CD36⁺ FBs that induced growth suppression of MDA-MB-231 breast cancer cells and determined their minimum effective concentrations. Here, we have expanded our analyses to include additional triple-negative cancer cell lines, BT549 and Hs578T, as well as HCC1937 carrying a BRCA1 mutation. We show that the ectopic addition of each of the three ligands to cancer-associated fibroblasts (CAFs) elevates the expression of CD36, as well as the adipogenic marker FABP4. Lastly, we show that an agonist antibody for one of the PENK receptors induces growth suppression of all cancer cell lines tested but not for non-transformed MCF10A cells. These results clearly suggest that proteins secreted from CD36⁺ FBs induce not only growth suppression of tumor cells through binding the cognate receptors but also increasing adipogenic markers of CAFs to reprogram tumor stroma. Full article

(This article belongs to the Special Issue Fibroblasts in Health and Disease)

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16 pages, 2093 KiB

Open AccessArticle

Human Papillary and Reticular Fibroblasts Show Distinct Functions on Tumor Behavior in 3D-Organotypic Cultures Mimicking Melanoma and HNSCC

by Shidi Wu, Marion Rietveld, Marieke Hogervorst, Frank de Gruijl, Sjoerd van der Burg, Maarten Vermeer, Remco van Doorn, Marij Welters and Abdoelwaheb El Ghalbzouri

Int. J. Mol. Sci. 2022, 23(19), 11651; https://doi.org/10.3390/ijms231911651 - 1 Oct 2022

Cited by 5 | Viewed by 2186

Abstract

Human dermis can be morphologically divided into the upper papillary and lower reticular dermis. Previously, we demonstrated that papillary (PFs) and reticular (RFs) fibroblasts show distinct morphology and gene expression profiles. Moreover, they differently affect tumor invasion and epithelial-to-mesenchymal transition (EMT) in in vitro 3D-organotypic cultures of cutaneous squamous cell carcinoma (cSCC). In this study, we examined if these distinct effects of PFs and RFs can be extrapolated in other epithelial/non-epithelial tumors such as melanoma and head and neck squamous cell carcinoma (HNSCC). To this end, 3D-Full-Thickness Models (FTMs) were established from melanoma (AN and M14) or HNSCC cell lines (UM-SCC19 and UM-SCC47) together with either PFs or RFs in the dermis. The interplay between tumor cells and different fibroblasts was investigated. We observed that all the tested tumor cell lines showed significantly stronger invasion in RF-FTMs compared to PF-FTMs. In addition, RF-FTMs demonstrated more tumor cell proliferation, EMT induction and basement membrane disruption. Interestingly, RFs started to express the cancer-associated fibroblast (CAF) biomarker α-SMA, indicating reciprocal interactions eventuating in the transition of RFs to CAFs. Collectively, in the melanoma and HNSCC FTMs, interaction of RFs with tumor cells promoted EMT and invasion, which was accompanied by differentiation of RFs to CAFs. Full article

(This article belongs to the Special Issue Fibroblasts in Health and Disease)

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14 pages, 3312 KiB

Open AccessArticle

ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis

by Ilaria Laudadio, Alex Bastianelli, Valerio Fulci, Claudia Carissimi, Eleonora Colantoni, Francesca Palone, Roberta Vitali, Elisa Lorefice, Salvatore Cucchiara, Anna Negroni and Laura Stronati

Int. J. Mol. Sci. 2022, 23(18), 10261; https://doi.org/10.3390/ijms231810261 - 6 Sep 2022

Cited by 9 | Viewed by 3151

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis. Full article

(This article belongs to the Special Issue Fibroblasts in Health and Disease)

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20 pages, 3172 KiB

Open AccessArticle

Proteomic Analysis Reveals Differential Expression Profiles in Idiopathic Pulmonary Fibrosis Cell Lines

by Juan Manuel Velázquez-Enríquez, Alma Aurora Ramírez-Hernández, Luis Manuel Sánchez Navarro, Itayetzi Reyes-Avendaño, Karina González-García, Cristian Jiménez-Martínez, Luis Castro-Sánchez, Xariss Miryam Sánchez-Chino, Verónica Rocío Vásquez-Garzón and Rafael Baltiérrez-Hoyos

Int. J. Mol. Sci. 2022, 23(9), 5032; https://doi.org/10.3390/ijms23095032 - 1 May 2022

Cited by 3 | Viewed by 4565

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible lung disorder of unknown cause. This disease is characterized by profibrotic activation of resident pulmonary fibroblasts resulting in aberrant deposition of extracellular matrix (ECM) proteins. However, although much is known about the pathophysiology of IPF, the cellular and molecular processes that occur and allow aberrant fibroblast activation remain an unmet need. To explore the differentially expressed proteins (DEPs) associated with aberrant activation of these fibroblasts, we used the IPF lung fibroblast cell lines LL97A (IPF-1) and LL29 (IPF-2), compared to the normal lung fibroblast cell line CCD19Lu (NL-1). Protein samples were quantified and identified using a label-free quantitative proteomic analysis approach by liquid chromatography-tandem mass spectrometry (LC-MS/MS). DEPs were identified after pairwise comparison, including all experimental groups. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein–Protein Interaction (PPI) network construction were used to interpret the proteomic data. Eighty proteins expressed exclusively in the IPF-1 and IPF-2 clusters were identified. In addition, 19 proteins were identified up-regulated in IPF-1 and 10 in IPF-2; 10 proteins were down-regulated in IPF-1 and 2 in IPF-2 when compared to the NL-1 proteome. Using the search tool for retrieval of interacting genes/proteins (STRING) software, a PPI network was constructed between the DEPs and the 80 proteins expressed exclusively in the IPF-2 and IPF-1 clusters, containing 115 nodes and 136 edges. The 10 hub proteins present in the IPP network were identified using the CytoHubba plugin of the Cytoscape software. GO and KEGG pathway analyses showed that the hub proteins were mainly related to cell adhesion, integrin binding, and hematopoietic cell lineage. Our results provide relevant information on DEPs present in IPF lung fibroblast cell lines when compared to the normal lung fibroblast cell line that could play a key role during IPF pathogenesis. Full article

(This article belongs to the Special Issue Fibroblasts in Health and Disease)

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11 pages, 1774 KiB

Open AccessArticle

Dedifferentiation of Human Cardiac Myofibroblasts Is Independent of Activation of COX-2/PGE₂ Pathway

by Vy Tran Luu, Sang Phan and Zhu-Qiu Jin

Int. J. Mol. Sci. 2022, 23(6), 3023; https://doi.org/10.3390/ijms23063023 - 11 Mar 2022

Cited by 1 | Viewed by 2581

Abstract

The differentiation of cardiac fibroblasts to myofibroblasts is considered to be a critical step in activation and progression of cardiac fibrosis in heart disease. TGF-β is one of the key cytokines that promotes transition of fibroblasts to myofibroblasts. Dedifferentiation of formed myofibroblasts or reversal of formed myofibroblasts to fibroblasts remains incompletely understood. Prostaglandin E₂ (PGE₂) has been shown to dedifferentiate human lung myofibroblasts. The role of activation of the COX-2/PGE₂ pathway in dedifferentiation of cardiac myofibroblasts remains unknown. Here, we show that phorbol 12-myristate 13-acetate (PMA) but not PGE₂ induces dedifferentiation of de novo adult human cardiac myofibroblasts stimulated by TGF-β1 from human cardiac fibroblasts as evidenced by reduced expression of α-smooth muscle actin (α-SMA). PMA remarkably increased endogenous levels of PGE₂ in human cardiac myofibroblasts. Pretreatment of myofibroblasts with NS-398, a selective COX-2 inhibitor, and PF-04418948, a selective PGE₂ receptor type 2 (EP2) antagonist, had no effect on expression of α-SMA nor abolished the dedifferentiation induced by PMA. Our results indicated that endogenous and exogenous PGE₂ has no effects on dedifferentiation of cardiac myofibroblasts. PMA-induced dedifferentiation of cardiac myofibroblast is independent of activation of COX-2 and PGE₂ pathway. The mechanism in PMA-induced reversal of cardiac myofibroblasts needs to be explored further. Full article

(This article belongs to the Special Issue Fibroblasts in Health and Disease)

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15 pages, 4352 KiB

Open AccessArticle

MicroRNA 148a Suppresses Tuberculous Fibrosis by Targeting NOX4 and POLDIP2

by Seong Ji Woo, Youngmi Kim, Harry Jung, Jae Jun Lee and Ji Young Hong

Int. J. Mol. Sci. 2022, 23(6), 2999; https://doi.org/10.3390/ijms23062999 - 10 Mar 2022

Cited by 6 | Viewed by 2447

Abstract

Extracellular matrix production by pleural mesothelial cells in response to Mycobacterium tuberculosis contributes to tuberculous fibrosis. NOX4 is involved in the pathogenesis of tuberculous fibrosis. In this study, we evaluated whether NOX4 gene-targeting microRNAs showed protective effects in tuberculosis fibrosis. TargetScan prediction software was used to identify candidate microRNAs that bind the 3′ UTRs of NOX4, and microRNA-148a (miR-148a) was selected as the best miRNA candidate. A repressed and forced expression assay in Met5A cells was performed to investigate the causal relationship between miR-148a and NOX4. The role of miR-148a in tuberculous pleural fibrosis was studied using a murine model of Mycobacterium bovis bacillus Calmette–Guérin (BCG) pleural infection. Heat-killed M. tuberculosis (HKMT) induces NOX4 and POLDIP2 expression. We demonstrated the inhibitory effect of miR-148a on NOX4 and POLDIP2 expression. The increased expression of miR-148a suppressed HKMT-induced collagen-1A synthesis in PMC cells. In the BCG pleurisy model, miR-148a significantly reduced fibrogenesis and epithelial mesenchymal transition. High levels of miR-148a in tuberculous pleural effusion can be interpreted as a self-limiting homeostatic response. Our data indicate that miR-148a may protect against tuberculous pleural fibrosis by regulating NOX4 and POLDIP2. Full article

(This article belongs to the Special Issue Fibroblasts in Health and Disease)

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23 pages, 21604 KiB

Open AccessArticle

Discrimination between NSIP- and IPF-Derived Fibroblasts Based on Multi-Parameter Characterization of Their Growth, Morphology and Physic-Chemical Properties

by Barbara Orzechowska, Kamil Awsiuk, Dawid Wnuk, Joanna Pabijan, Tomasz Stachura, Jerzy Soja, Krzysztof Sładek and Joanna Raczkowska

Int. J. Mol. Sci. 2022, 23(4), 2162; https://doi.org/10.3390/ijms23042162 - 15 Feb 2022

Cited by 3 | Viewed by 2625

Abstract

Background: The aim of the research presented here was to find a set of parameters enabling discrimination between three types of fibroblasts, i.e., healthy ones and those derived from two disorders mimicking each other: idiopathic pulmonary fibrosis (IPF), and nonspecific interstitial pneumonia (NSIP). Methods: The morphology and growth of cells were traced using fluorescence microscopy and analyzed quantitatively using cell proliferation and substrate cytotoxicity indices. The viability of cells was recorded using MTS assays, and their stiffness was examined using atomic force microscopy (AFM) working in force spectroscopy (FS) mode. To enhance any possible difference in the examined parameters, experiments were performed with cells cultured on substrates of different elasticities. Moreover, the chemical composition of cells was determined using time-of-flight secondary ion mass spectrometry (ToF-SIMS), combined with sophisticated analytical tools, i.e., Multivariate Curve Resolution (MCR) and Principal Component Analysis (PCA). Results: The obtained results demonstrate that discrimination between cell lines derived from healthy and diseased patients is possible based on the analysis of the growth of cells, as well as their physical and chemical properties. In turn, the comparative analysis of the cellular response to altered stiffness of the substrates enables the identification of each cell line, including distinguishing between IPF- and NSIP-derived fibroblasts. Full article

(This article belongs to the Special Issue Fibroblasts in Health and Disease)

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