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17 pages, 2536 KiB

Open AccessArticle

Interstitial Macrophages Lead Early Stages of Bleomycin-Induced Lung Fibrosis and Induce Fibroblasts Activation

by Sofia Libório-Ramos, Catarina Barbosa-Matos, Raquel Fernandes, Caroline Borges-Pereira and Sandra Costa

Cells 2023, 12(3), 402; https://doi.org/10.3390/cells12030402 - 24 Jan 2023

Cited by 9 | Viewed by 3322

Abstract

A progressive fibrosing phenotype is critical in several lung diseases. It is irreversible and associated with early patient mortality. Growing evidence has revealed pulmonary macrophages’ role as modulators of the fibrotic processes. The proportion, phenotype, and function of alveolar (AM) and interstitial macrophages [...] Read more.

A progressive fibrosing phenotype is critical in several lung diseases. It is irreversible and associated with early patient mortality. Growing evidence has revealed pulmonary macrophages’ role as modulators of the fibrotic processes. The proportion, phenotype, and function of alveolar (AM) and interstitial macrophages (IM) at the early stages of bleomycin-induced pulmonary fibrosis have not been clearly described. In this way, our study aimed to characterize these macrophage populations and investigate the effect on fibroblast activation. C57BL/6 mice were intratracheally injected with bleomycin and were sacrificed at day 3, 5, and 7 for the performance of flow cytometry and fluorescent-activated cell sorting analysis for protein and gene expression quantification. After bleomycin administration, the proportion of IM was significantly higher than that of AM, which showed a decay during the inflammatory phase, and peaked at day 7. At day 7 of the inflammatory phase, AM started shifting their phenotype from M1-like towards M2, while IM showed a M2-like phenotype. Conditioned medium derived from IM sorted at day 7 induced fibroblast activation and differentiation in myofibroblasts in vitro. Our findings indicate that IM are the largest macrophage population at the early stages of experimental pulmonary fibrosis and are secreted mediators able to activate fibroblasts, pointing to macrophage modulation as a potential therapeutic strategy to restrain progressive fibrosing lung disorders. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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16 pages, 2402 KiB

Open AccessArticle

Lack of ZNF365 Drives Senescence and Exacerbates Experimental Lung Fibrosis

by Juan Urista, Mariel Maldonado, Fernanda Toscano-Marquez, Remedios Ramírez, Yalbi Itzel Balderas-Martínez, Carina Becerril, Yair Romero, Moisés Selman and Annie Pardo

Cells 2022, 11(18), 2848; https://doi.org/10.3390/cells11182848 - 13 Sep 2022

Cited by 4 | Viewed by 2993

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant activation of the alveolar epithelium, the expansion of the fibroblast population, and the accumulation of extracellular matrix. Global gene expression of human lung fibroblasts stimulated with TGFβ-1, a strong fibrotic mediator revealed the overexpression of [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant activation of the alveolar epithelium, the expansion of the fibroblast population, and the accumulation of extracellular matrix. Global gene expression of human lung fibroblasts stimulated with TGFβ-1, a strong fibrotic mediator revealed the overexpression of ZNF365, a zinc finger protein implicated in cell cycle control and telomere stabilization. We evaluated the expression and localization of ZNF365 in IPF lungs and in the fibrotic response induced by bleomycin in WT and deficient mice of the orthologous gene Zfp365. In IPF, ZNF365 was overexpressed and localized in fibroblasts/myofibroblasts and alveolar epithelium. Bleomycin-induced lung fibrosis showed an upregulation of Zfp365 localized in lung epithelium and stromal cell populations. Zfp365 KO mice developed a significantly higher fibrotic response compared with WT mice by morphology and hydroxyproline content. Silencing ZNF365 in human lung fibroblasts and alveolar epithelial cells induced a significant reduction of growth rate and increased senescence markers, including Senescence Associated β Galactosidase activity, p53, p21, and the histone variant γH2AX. Our findings demonstrate that ZNF365 is upregulated in IPF and experimental lung fibrosis and suggest a protective role since its absence increases experimental lung fibrosis mechanistically associated with the induction of cell senescence. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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16 pages, 3875 KiB

Open AccessArticle

Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis

by Jia Wen, Baihai Jiao, Melanie Tran and Yanlin Wang

Cells 2022, 11(17), 2762; https://doi.org/10.3390/cells11172762 - 5 Sep 2022

Cited by 15 | Viewed by 3056

Abstract

The TGF-β/Smad3 signaling pathway is an important process in the pathogenesis of kidney fibrosis. However, the molecular mechanisms are not completely elucidated. The current study examined the functional role of S100A4 in regulating TGF-β/Smad3 signaling in fibroblast activation and kidney fibrosis development. S100A4 [...] Read more.

The TGF-β/Smad3 signaling pathway is an important process in the pathogenesis of kidney fibrosis. However, the molecular mechanisms are not completely elucidated. The current study examined the functional role of S100A4 in regulating TGF-β/Smad3 signaling in fibroblast activation and kidney fibrosis development. S100A4 was upregulated in the kidney in a murine model of renal fibrosis induced by folic acid nephropathy. Further, S100A4 was predominant in the tubulointerstitial cells of the kidney. Pharmacological inhibition of S100A4 with niclosamide significantly attenuated fibroblast activation, decreased collagen content, and reduced extracellular matrix protein expression in folic acid nephropathy. Overexpression of S100A4 in cultured renal fibroblasts significantly facilitated TGF-β1-induced activation of fibroblasts by increasing the expression of α-SMA, collagen-1 and fibronectin. In contrast, S100A4 knockdown prevented TGF-β1-induced activation of fibroblast and transcriptional activity of Smad3. Mechanistically, S100A4 interacts with Smad3 to stabilize the Smad3/Smad4 complex and promotes their translocation to the nucleus. In conclusion, S100A4 facilitates TGF-β signaling via interaction with Smad3 and promotes kidney fibrosis development. Manipulating S100A4 may provide a beneficial therapeutic strategy for chronic kidney disease. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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14 pages, 2978 KiB

Open AccessArticle

Induction of Pro-Fibrotic CLIC4 in Dermal Fibroblasts by TGF-β/Wnt3a Is Mediated by GLI2 Upregulation

by Christopher W. Wasson, Begoña Caballero-Ruiz, Justin Gillespie, Emma Derrett-Smith, Jamel Mankouri, Christopher P. Denton, Gianluca Canettieri, Natalia A. Riobo-Del Galdo and Francesco Del Galdo

Cells 2022, 11(3), 530; https://doi.org/10.3390/cells11030530 - 3 Feb 2022

Cited by 7 | Viewed by 2529

Abstract

Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts (CAF). CLIC4 expression and activity are regulated by TGF-β signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt-3a [...] Read more.

Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts (CAF). CLIC4 expression and activity are regulated by TGF-β signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt-3a and Hedgehog (Hh) signalling in fibrosis, we investigated their role in CLIC4 upregulation. Here, we show that TGF-β/SMAD3 co-operates with Wnt3a/β-catenin and Smoothened/GLI signalling to drive CLIC4 expression in normal dermal fibroblasts, and that the inhibition of β-catenin and GLI expression or activity abolishes TGF-β/SMAD3-dependent CLIC4 induction. We further show that the expression of the pro-fibrotic marker α-smooth muscle actin strongly correlates with CLIC4 expression in dermal fibroblasts. Further investigations revealed that the inhibition of CLIC4 reverses morphogen-dependent fibroblast activation. Our data highlights that CLIC4 is a common downstream target of TGF-β, Hh, and Wnt-3a through signalling crosstalk and we propose a potential therapeutic avenue using CLIC4 inhibitors Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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9 pages, 262 KiB

Open AccessArticle

Utility of Telomerase Gene Mutation Testing in Patients with Idiopathic Pulmonary Fibrosis in Routine Practice

by Julij Šelb, Katarina Osolnik, Izidor Kern, Peter Korošec and Matija Rijavec

Cells 2022, 11(3), 372; https://doi.org/10.3390/cells11030372 - 22 Jan 2022

Cited by 2 | Viewed by 2813

Abstract

Recent studies have suggested that causative variants in telomerase complex genes (TCGs) are present in around 10% of individuals with idiopathic pulmonary fibrosis (IPF) regardless of family history of the disease. However, the studies used a case-control rare variant enrichment study design which [...] Read more.

Recent studies have suggested that causative variants in telomerase complex genes (TCGs) are present in around 10% of individuals with idiopathic pulmonary fibrosis (IPF) regardless of family history of the disease. However, the studies used a case-control rare variant enrichment study design which is not directly translatable to routine practice. To validate the prevalence results and to establish the individual level, routine clinical practice, and utility of those results we performed next generation sequencing of TCGs on a cohort of well-characterized consecutive individuals with IPF (diagnosis established according to ATS/ERS/JRS/ALAT guidelines). Of 27 IPF patients, three had a family history of idiopathic interstitial pneumonia (familial IPF) and 24 did not (sporadic IPF). Pathogenic/likely-pathogenic variants (according to American College of Medical Genetics criteria) in TCG were found in three individuals (11.1%) of the whole cohort; specifically, they were present in 2 out of 24 (8.3%) of the sporadic and in 1 out of 3 (33.3%) of the patients with familial IPF. Our results, which were established on an individual-patient level study design and in routine clinical practice (as opposed to the case-control study design), are roughly in line with the around 10% prevalence of causative TCG variants in patients with IPF. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

18 pages, 7017 KiB

Open AccessFeature PaperArticle

Combined Assessment of the Tumor–Stroma Ratio and Tumor Immune Cell Infiltrate for Immune Checkpoint Inhibitor Therapy Response Prediction in Colon Cancer

by Cor J. Ravensbergen, Meaghan Polack, Jessica Roelands, Stijn Crobach, Hein Putter, Hans Gelderblom, Rob A. E. M. Tollenaar and Wilma E. Mesker

Cells 2021, 10(11), 2935; https://doi.org/10.3390/cells10112935 - 28 Oct 2021

Cited by 15 | Viewed by 3114

Abstract

The best current biomarker strategies for predicting response to immune checkpoint inhibitor (ICI) therapy fail to account for interpatient variability in response rates. The histologic tumor–stroma ratio (TSR) quantifies intratumoral stromal content and was recently found to be predictive of response to neoadjuvant [...] Read more.

The best current biomarker strategies for predicting response to immune checkpoint inhibitor (ICI) therapy fail to account for interpatient variability in response rates. The histologic tumor–stroma ratio (TSR) quantifies intratumoral stromal content and was recently found to be predictive of response to neoadjuvant therapy in multiple cancer types. In the current work, we predicted the likelihood of ICI therapy responsivity of 335 therapy-naive colon adenocarcinoma tumors from The Cancer Genome Atlas, using bioinformatics approaches. The TSR was scored on diagnostic tissue slides, and tumor-infiltrating immune cells (TIICs) were inferred from transcriptomic data. Tumors with high stromal content demonstrated increased T regulatory cell infiltration (p = 0.014) but failed to predict ICI therapy response. Consequently, we devised a hybrid tumor microenvironment classification of four stromal categories, based on histological stromal content and transcriptomic-deconvoluted immune cell infiltration, which was associated with previously established transcriptomic and genomic biomarkers for ICI therapy response. By integrating these biomarkers, stroma-low/immune-high tumors were predicted to be most responsive to ICI therapy. The framework described here provides evidence for expansion of current histological TIIC quantification to include the TSR as a novel, easy-to-use biomarker for the prediction of ICI therapy response. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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15 pages, 6052 KiB

Open AccessArticle

Different Patterns of Kidney Fibrosis Are Indicative of Injury to Distinct Renal Compartments

by Désirée Tampe, Laura Schridde, Peter Korsten, Philipp Ströbel, Michael Zeisberg, Samy Hakroush and Björn Tampe

Cells 2021, 10(8), 2014; https://doi.org/10.3390/cells10082014 - 6 Aug 2021

Cited by 9 | Viewed by 4540

Abstract

Kidney fibrosis is a common manifestation and hallmark of a wide variety of chronic kidney disease (CKD) that appears in different morphological patterns, suggesting distinct pathogenic causes. Broad macroscopically visible scars are the sequelae of severe focal injury and complete parenchymal destruction, reflecting [...] Read more.

Kidney fibrosis is a common manifestation and hallmark of a wide variety of chronic kidney disease (CKD) that appears in different morphological patterns, suggesting distinct pathogenic causes. Broad macroscopically visible scars are the sequelae of severe focal injury and complete parenchymal destruction, reflecting a wound healing response as a consequence of infarction. In the kidney, chronic glomerular injury leads to atrophy of the corresponding tubule, degeneration of this specific nephron, and finally interstitial fibrosis/tubular atrophy (IF/TA). Compared to this glomerulus-induced focal replacement scar, diffuse fibrosis independent of tubular atrophy appears to be a different pathogenic process. Kidney fibrosis appears to develop in a compartment-specific manner, but whether focal and diffuse fibrosis has distinct characteristics associated with other glomerular or tubulointerstitial lesions remains elusive. In the present study, we aimed to analyze renal fibrotic patterns related to renal lesions, which directly contribute to renal fibrogenesis, to unravel fibrotic patterns and manifestations upon damage to distinct renal compartments. Patterns of kidney fibrosis were analyzed in experimental models of CKD and various renal pathologies in correlation with histopathological and ultrastructural findings. After the induction of isolated crescentic glomerulonephritis (GN) in nephrotoxic serum-nephritis (NTN), chronic glomerular damage resulted in predominantly focal fibrosis adjacent to atrophic tubules. By contrast, using unilateral ureteral obstruction (UUO) as a model of primary injury to the tubulointerstitial compartment revealed diffuse fibrosis as the predominant pattern of chronic lesions. Finally, folic acid-induced nephropathy (FAN) as a model of primary tubular injury with consecutive tubular atrophy independent of chronic glomerular damage equally induced predominant focal IF/TA. By analyzing several renal pathologies, our data also suggest that focal and diffuse fibrosis appear to contribute as chronic lesions in the majority of human renal disease, mainly being present in antineutrophil cytoplasmic antibody (ANCA)-associated GN, lupus nephritis, and IgA nephropathy (IgAN). Focal IF/TA correlated with glomerular damage and irreversible injury to nephrons, whereas diffuse fibrosis in ANCA GN was associated explicitly with interstitial inflammation independent of glomerular damage and nephron loss. Ultrastructural analysis of focal IF/TA versus diffuse fibrosis revealed distinct matrix compositions, further supported by different collagen signatures in transcriptome datasets. With regard to long-term renal outcome, only the extent of focal IF/TA correlated with the development of end-stage kidney disease (ESKD) in ANCA GN. In contrast, diffuse kidney fibrosis did not associate with the long-term renal outcome. In conclusion, we here provide evidence that a focal pattern of kidney fibrosis seems to be associated with nephron loss and replacement scarring. In contrast, a diffuse pattern of kidney fibrosis appears to result from primary interstitial inflammation and injury. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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Review

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21 pages, 11104 KiB

Open AccessReview

Fibrosis Is a Basement Membrane-Related Disease in the Cornea: Injury and Defective Regeneration of Basement Membranes May Underlie Fibrosis in Other Organs

by Steven E. Wilson

Cells 2022, 11(2), 309; https://doi.org/10.3390/cells11020309 - 17 Jan 2022

Cited by 18 | Viewed by 4177

Abstract

Every organ develops fibrosis that compromises functions in response to infections, injuries, or diseases. The cornea is a relatively simple, avascular organ that offers an exceptional model to better understand the pathophysiology of the fibrosis response. Injury and defective regeneration of the epithelial [...] Read more.

Every organ develops fibrosis that compromises functions in response to infections, injuries, or diseases. The cornea is a relatively simple, avascular organ that offers an exceptional model to better understand the pathophysiology of the fibrosis response. Injury and defective regeneration of the epithelial basement membrane (EBM) or the endothelial Descemet’s basement membrane (DBM) triggers the development of myofibroblasts from resident corneal fibroblasts and bone marrow-derived blood borne fibrocytes due to the increased entry of TGF beta-1/-2 into the stroma from the epithelium and tears or residual corneal endothelium and aqueous humor. The myofibroblasts, and disordered extracellular matrix these cells produce, persist until the source of injury is removed, the EBM and/or DBM are regenerated, or replaced surgically, resulting in decreased stromal TGF beta requisite for myofibroblast survival. A similar BM injury-related pathophysiology can underly the development of fibrosis in other organs such as skin and lung. The normal liver does not contain traditional BMs but develops sinusoidal endothelial BMs in many fibrotic diseases and models. However, normal hepatic stellate cells produce collagen type IV and perlecan that can modulate TGF beta localization and cognate receptor binding in the space of Dissé. BM-related fibrosis is deserving of more investigation in all organs. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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