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Macrophages are central to healing and polarize into pro-inflammatory M1 and anti-inflammatory M2 subsets, influencing multiple repair stages. They also guide fibroblasts during extracellular matrix degradation, synthesis, and rearrangement, yet the direct impact of paracrine signals from distinct macrophage phenotypes on fibroblast-driven tissue remodelling is unclear. Therefore, this study investigates how M1, M2a, and M2c macrophage-derived factors affect fibroblast remodelling capacity in vitro.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/macrophage-paracrine-signalling-differentially-affects-fibroblast-induced-collagenous-tissue-remodelling-original-article/455608/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/macrophage-paracrine-signalling-differentially-affects-fibroblast-induced-collagenous-tissue-remodelling-original-article/455608.png","ImageObject",300,407,{"name":92,"@type":93},"Ezra","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-07","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What was the study’s main objective?","Question",{"text":112,"@type":113},"To determine how paracrine factors secreted by M1, M2a, and M2c macrophages affect fibroblast-driven structural tissue remodelling in an in vitro model.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were macrophage and fibroblast interactions modeled in this research?",{"text":117,"@type":113},"Macrophages were polarized in vitro, and their conditioned or cytokine-enriched media containing macrophage-secreted factors were added to fibroblast-populated reconstituted collagen tissues.",{"name":119,"@type":110,"acceptedAnswer":120},"What effects did macrophage-conditioned media have on fibroblast-driven tissue remodelling?",{"text":121,"@type":113},"Macrophage-conditioned media changed fibroblast-induced tissue compaction across all macrophage subsets, and the presence of macrophage polarizing factors, particularly LPS/IFNc and high serum levels, influenced compaction and matrix remodelling gene expression.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},455608,1790812120,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099514068035,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Tissue Eng Regen Med (2026) 23(1):125–142 Online ISSN 2212-5469  \n[https://doi.org/10.1007/s13770-025-00766-1](https://doi.org/10.1007/s13770-025-00766-1)  \nORIGINAL ARTICLE  \nMacrophage Paracrine Signalling Differentially Affects Fibroblast-Induced Collagenous Tissue Remodelling  \nHannah F. M. Brouwer1,2 • Amal K. Mansoor1,2 • Sylvia Dekker1 •  \nCarlijn V. C. Bouten1,2 • Keita Ito1,2 • Jasper Foolen1,2 • Anthal I. P. M. Smits1,2   \nReceived: 23 May 2025/Revised: 5 September 2025/Accepted: 9 September 2025/Published online: 28 November 2025 􀀂 The Author(s) 2025  \nAbstract  \nBACKGROUND Upon injury, tissue repair often leads to a loss in functionality, organisation, and structure. The immune system, particularly macrophages, is crucial during tissue healing. Macrophages polarise into pro-inflammatory M1 and anti-inflammatory M2 subsets, regulating various stages of tissue healing. Macrophages steer fibroblasts in the process of extracellular matrix degradation, synthesis, and rearrangement. However, the direct role of paracrine signalling by different macrophage phenotypes on fibroblast-induced structural tissue remodelling remains elusive. Therefore, this study aimed to explore how paracrine factors from M1, M2a, and M2c macrophages affect fibroblast remodelling abilities in an in vitro model system.  \nMETHODS Macrophages were polarised in vitro, and their conditioned medium or cytokine-enriched medium containing specific macrophage-secreted factors was added to fibroblast-populated reconstituted collagen tissues.  \nRESULTS Macrophage-conditioned media led to changes in fibroblast-induced tissue compaction for all macrophage subsets. The presence of macrophage polarising factors in the conditioned medium, particularly LPS/IFNc, and high serum levels directly affected tissue compaction and matrix remodelling gene expression. Without these confounding factors, M1 cytokine-enriched medium led to reduced tissue compaction when compared to M2a/M2c cytokine-enriched media. MMP activity analysis showed that matrix degradation likely contributed to tissue compaction.  \nCONCLUSION Factors secreted by M1 macrophages resulted in reduced tissue compaction compared to M2a/M2c macrophages in an in vitro model of tissue remodelling, suggesting a diminished capacity for fibroblasts to remodel the extracellular matrix. Importantly, factors to polarize macrophages and serum are regarded as confounding factors in studying the effect of paracrine signalling by macrophages on tissue remodelling.  \nKeywords Macrophage polarisation 􀀂 Tissue engineering 􀀂 Collagen remodelling  \nHannah F. M. Brouwer and Amal K. Mansoor contributed equally.  \n& Jasper Foolen [JFoolen@tue.nl](JFoolen@tue.nl)  \n& Anthal I. P. M. Smits [a.i.p.m.smits@tue.nl](a.i.p.m.smits@tue.nl)  \n1 Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven, The Netherlands  \n2 Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands  \n1 Introduction  \nAfter tissue injury, the repair process is complex and multifaceted, aiming to restore both the architecture and function of the affected tissue [1] . One common limitation of tissue repair is the inability to fully regain original strength, organisation, and functionality. This loss of tissue structural integrity is often seen as a failure of functional tissue remodelling due to an imbalance between extracellular matrix (ECM) degeneration and synthesis. In tendon healing, for example, tendons often heal by depositing  \nexcessive, disorganised ECM, which is in contrast to the naturally present strong tissue anisotropy [2] . Similarly, in skin, improper tissue repair creates hypertrophic scars or keloids, which are painful, create movement restrictions, and are often aesthetically undesirable [3, 4] . This failure in proper matrix remodelling can result in mechanically inferior tissue, pain, decreased function, and eventual risk of (re-)rupture.","cbCaiqv5dVKNITU6","https://ap.wps.com/l/cbCaiqv5dVKNITU6","pdf",5614308,18,"English","# Introduction\n## Macrophages and tissue remodelling phases\n## Macrophage phenotypes (M1, M2a, M2c)\n# Abstract\n## Background\n## Methods\n## Results\n## Conclusion","[{\"question\":\"What was the study’s main objective?\",\"answer\":\"To determine how paracrine factors secreted by M1, M2a, and M2c macrophages affect fibroblast-driven structural tissue remodelling in an in vitro model.\"},{\"question\":\"How were macrophage and fibroblast interactions modeled in this research?\",\"answer\":\"Macrophages were polarized in vitro, and their conditioned or cytokine-enriched media containing macrophage-secreted factors were added to fibroblast-populated reconstituted collagen tissues.\"},{\"question\":\"What effects did macrophage-conditioned media have on fibroblast-driven tissue remodelling?\",\"answer\":\"Macrophage-conditioned media changed fibroblast-induced tissue compaction across all macrophage subsets, and the presence of macrophage polarizing factors, particularly LPS/IFNc and high serum levels, influenced compaction and matrix remodelling gene expression.\"}]","Macrophage Paracrine Signalling Differentially Affects Fibroblast-Induced Collagenous Tissue Remodelling - Original Article | PDF",1790743595,45]