Three dimensional fibrotic extracellular matrix directs microenvironment fiber remodeling by fibroblasts.

Autor: Nizamoglu M; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands. Electronic address: m.nizamoglu@umcg.nl., Alleblas F; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands., Koster T; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands., Borghuis T; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands., Vonk JM; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands., Thomas MJ; Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany., White ES; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, United States., Watson CK; Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany., Timens W; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands., El Kasmi KC; Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany., Melgert BN; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands; University of Groningen, Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, Groningen, the Netherlands., Heijink IH; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, the Netherlands., Burgess JK; University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, W.J. Kolff Institute for Biomedical Engineering and Materials Science-FB41, Groningen, the Netherlands. Electronic address: j.k.burgess@umcg.nl.
Jazyk: angličtina
Zdroj: Acta biomaterialia [Acta Biomater] 2024 Mar 15; Vol. 177, pp. 118-131. Date of Electronic Publication: 2024 Feb 11.
DOI: 10.1016/j.actbio.2024.02.008
Abstrakt: Idiopathic pulmonary fibrosis (IPF), for which effective treatments are limited, results in excessive and disorganized deposition of aberrant extracellular matrix (ECM). An altered ECM microenvironment is postulated to contribute to disease progression through inducing profibrotic behavior of lung fibroblasts, the main producers and regulators of ECM. Here, we examined this hypothesis in a 3D in vitro model system by growing primary human lung fibroblasts in ECM-derived hydrogels from non-fibrotic (control) or IPF lung tissue. Using this model, we compared how control and IPF lung-derived fibroblasts responded in control and fibrotic microenvironments in a combinatorial manner. Culture of fibroblasts in fibrotic hydrogels did not alter in the overall amount of collagen or glycosaminoglycans but did cause a drastic change in fiber organization compared to culture in control hydrogels. High-density collagen percentage was increased by control fibroblasts in IPF hydrogels at day 7, but decreased at day 14. In contrast, IPF fibroblasts only decreased the high-density collagen percentage at day 14, which was accompanied by enhanced fiber alignment in IPF hydrogels. Similarly, stiffness of fibrotic hydrogels was increased only by control fibroblasts by day 14 while those of control hydrogels were not altered by fibroblasts. These data highlight how the ECM-remodeling responses of fibroblasts are influenced by the origin of both the cells and the ECM. Moreover, by showing how the 3D microenvironment plays a crucial role in directing cells, our study paves the way in guiding future investigations examining fibrotic processes with respect to ECM remodeling responses of fibroblasts. STATEMENT OF SIGNIFICANCE: In this study, we investigated the influence of the altered extracellular matrix (ECM) in Idiopathic Pulmonary Fibrosis (IPF), using a 3D in vitro model system composed of ECM-derived hydrogels from both IPF and control lungs, seeded with human IPF and control lung fibroblasts. While our results indicated that fibrotic microenvironment did not change the overall collagen or glycosaminoglycan content, it resulted in a dramatically alteration of fiber organization and mechanical properties. Control fibroblasts responded differently from IPF fibroblasts, highlighting the unique instructive role of the fibrotic ECM and the interplay with fibroblast origin. These results underscore the importance of 3D microenvironments in guiding pro-fibrotic responses, offering potential insights for future IPF therapies as well as other fibrotic diseases and cancer.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.N., T.K., B.N.M., I.H.H. and J.K.B. receive unrestricted research funds from Boehringer Ingelheim. M.J.T., C.K.W., E.S.W. and K.C.K. are employees of Boehringer Ingelheim.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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