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Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models

FRANCESCA PARADISO, Marcos Quintela Vazquez, Stefania Lenna, Stefano Serpelloni, David James, Sergio Caserta, Steve Conlan Orcid Logo, Lewis Francis Orcid Logo, Francesca Taraballi Orcid Logo

Macromolecular Bioscience, Volume: 22, Issue: 4, Start page: 2100450

Swansea University Authors: FRANCESCA PARADISO, Marcos Quintela Vazquez, David James, Steve Conlan Orcid Logo, Lewis Francis Orcid Logo

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DOI (Published version): 10.1002/mabi.202100450

Abstract

Fibrosis and solid tumor progression are closely related, with both involving pathways associated with chronic wound dysregulation. Fibroblasts contribute to extracellular matrix (ECM) remodeling in these processes, a crucial step in scarring, organ failure, and tumor growth, but little is known abo...

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Published in: Macromolecular Bioscience
ISSN: 1616-5187 1616-5195
Published: Wiley 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa59159
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Fibroblasts contribute to extracellular matrix (ECM) remodeling in these processes, a crucial step in scarring, organ failure, and tumor growth, but little is known about the biophysical evolution of remodeling regulation during the development and progression of matrix-related diseases including fibrosis and cancer. A 3D collagen-based scaffold model is employed here to mimic mechanical changes in normal (2 kPa, soft) versus advanced pathological (12 kPa, stiff) tissues. Activated fibroblasts grown on stiff scaffolds show lower migration and increased cell circularity compared to those on soft scaffolds. This is reflected in gene expression profiles, with cells cultured on stiff scaffolds showing upregulated DNA replication, DNA repair, and chromosome organization gene clusters, and a concomitant loss of ability to remodel and deposit ECM. Soft scaffolds can reproduce biophysically meaningful microenvironments to investigate early stage processes in wound healing and tumor niche formation, while stiff scaffolds can mimic advanced fibrotic and cancer stages. These results establish the need for tunable, affordable 3D scaffolds as platforms for aberrant stroma research and reveal the contribution of physiological and pathological microenvironment biomechanics to gene expression changes in the stromal compartment.</abstract><type>Journal Article</type><journal>Macromolecular Bioscience</journal><volume>22</volume><journalNumber>4</journalNumber><paginationStart>2100450</paginationStart><paginationEnd/><publisher>Wiley</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1616-5187</issnPrint><issnElectronic>1616-5195</issnElectronic><keywords>3D model; cancer; fibrosis; mechanics; microenvironment; stroma</keywords><publishedDay>1</publishedDay><publishedMonth>4</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-04-01</publishedDate><doi>10.1002/mabi.202100450</doi><url/><notes/><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><apcterm/><funders>European Regional Development Fund through the Welsh Government</funders><projectreference/><lastEdited>2022-08-04T11:25:05.8566509</lastEdited><Created>2022-01-12T11:44:28.9226306</Created><path><level id="1">Swansea University Medical School</level><level id="2">Medicine</level></path><authors><author><firstname>FRANCESCA</firstname><surname>PARADISO</surname><order>1</order></author><author><firstname>Marcos</firstname><surname>Quintela Vazquez</surname><order>2</order></author><author><firstname>Stefania</firstname><surname>Lenna</surname><order>3</order></author><author><firstname>Stefano</firstname><surname>Serpelloni</surname><order>4</order></author><author><firstname>David</firstname><surname>James</surname><orcid/><order>5</order></author><author><firstname>Sergio</firstname><surname>Caserta</surname><order>6</order></author><author><firstname>Steve</firstname><surname>Conlan</surname><orcid>0000-0002-2562-3461</orcid><order>7</order></author><author><firstname>Lewis</firstname><surname>Francis</surname><orcid>0000-0002-7803-7714</orcid><order>8</order></author><author><firstname>Francesca</firstname><surname>Taraballi</surname><orcid>0000-0002-4959-1169</orcid><order>9</order></author></authors><documents><document><filename>59159__22584__61516fe01547433b8714a7eaae818c5d.pdf</filename><originalFilename>59159.pdf</originalFilename><uploaded>2022-03-14T12:13:07.0605431</uploaded><type>Output</type><contentLength>3304515</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2022 The Authors. 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spelling v2 59159 2022-01-12 Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models 31f23b060034e6cfeb7ae4bbbb86f9dc FRANCESCA PARADISO FRANCESCA PARADISO true false 29d006fa16d293ca29762fce9c356f8e Marcos Quintela Vazquez Marcos Quintela Vazquez true false 31b39419835be9525450cf1420e63996 David James David James true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false 2022-01-12 Fibrosis and solid tumor progression are closely related, with both involving pathways associated with chronic wound dysregulation. Fibroblasts contribute to extracellular matrix (ECM) remodeling in these processes, a crucial step in scarring, organ failure, and tumor growth, but little is known about the biophysical evolution of remodeling regulation during the development and progression of matrix-related diseases including fibrosis and cancer. A 3D collagen-based scaffold model is employed here to mimic mechanical changes in normal (2 kPa, soft) versus advanced pathological (12 kPa, stiff) tissues. Activated fibroblasts grown on stiff scaffolds show lower migration and increased cell circularity compared to those on soft scaffolds. This is reflected in gene expression profiles, with cells cultured on stiff scaffolds showing upregulated DNA replication, DNA repair, and chromosome organization gene clusters, and a concomitant loss of ability to remodel and deposit ECM. Soft scaffolds can reproduce biophysically meaningful microenvironments to investigate early stage processes in wound healing and tumor niche formation, while stiff scaffolds can mimic advanced fibrotic and cancer stages. These results establish the need for tunable, affordable 3D scaffolds as platforms for aberrant stroma research and reveal the contribution of physiological and pathological microenvironment biomechanics to gene expression changes in the stromal compartment. Journal Article Macromolecular Bioscience 22 4 2100450 Wiley 1616-5187 1616-5195 3D model; cancer; fibrosis; mechanics; microenvironment; stroma 1 4 2022 2022-04-01 10.1002/mabi.202100450 COLLEGE NANME COLLEGE CODE Swansea University European Regional Development Fund through the Welsh Government 2022-08-04T11:25:05.8566509 2022-01-12T11:44:28.9226306 Swansea University Medical School Medicine FRANCESCA PARADISO 1 Marcos Quintela Vazquez 2 Stefania Lenna 3 Stefano Serpelloni 4 David James 5 Sergio Caserta 6 Steve Conlan 0000-0002-2562-3461 7 Lewis Francis 0000-0002-7803-7714 8 Francesca Taraballi 0000-0002-4959-1169 9 59159__22584__61516fe01547433b8714a7eaae818c5d.pdf 59159.pdf 2022-03-14T12:13:07.0605431 Output 3304515 application/pdf Version of Record true © 2022 The Authors. This is an open access article under the terms of the Creative Commons Attribution License true eng http://creativecommons.org/licenses/by/4.0/
title Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models
spellingShingle Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models
FRANCESCA PARADISO
Marcos Quintela Vazquez
David James
Steve Conlan
Lewis Francis
title_short Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models
title_full Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models
title_fullStr Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models
title_full_unstemmed Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models
title_sort Studying Activated Fibroblast Phenotypes and Fibrosis‐Linked Mechanosensing Using 3D Biomimetic Models
author_id_str_mv 31f23b060034e6cfeb7ae4bbbb86f9dc
29d006fa16d293ca29762fce9c356f8e
31b39419835be9525450cf1420e63996
0bb6bd247e32fb4249de62c0013b51cb
10f61f9c1248951c1a33f6a89498f37d
author_id_fullname_str_mv 31f23b060034e6cfeb7ae4bbbb86f9dc_***_FRANCESCA PARADISO
29d006fa16d293ca29762fce9c356f8e_***_Marcos Quintela Vazquez
31b39419835be9525450cf1420e63996_***_David James
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
author FRANCESCA PARADISO
Marcos Quintela Vazquez
David James
Steve Conlan
Lewis Francis
author2 FRANCESCA PARADISO
Marcos Quintela Vazquez
Stefania Lenna
Stefano Serpelloni
David James
Sergio Caserta
Steve Conlan
Lewis Francis
Francesca Taraballi
format Journal article
container_title Macromolecular Bioscience
container_volume 22
container_issue 4
container_start_page 2100450
publishDate 2022
institution Swansea University
issn 1616-5187
1616-5195
doi_str_mv 10.1002/mabi.202100450
publisher Wiley
college_str Swansea University Medical School
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hierarchy_top_id swanseauniversitymedicalschool
hierarchy_top_title Swansea University Medical School
hierarchy_parent_id swanseauniversitymedicalschool
hierarchy_parent_title Swansea University Medical School
department_str Medicine{{{_:::_}}}Swansea University Medical School{{{_:::_}}}Medicine
document_store_str 1
active_str 0
description Fibrosis and solid tumor progression are closely related, with both involving pathways associated with chronic wound dysregulation. Fibroblasts contribute to extracellular matrix (ECM) remodeling in these processes, a crucial step in scarring, organ failure, and tumor growth, but little is known about the biophysical evolution of remodeling regulation during the development and progression of matrix-related diseases including fibrosis and cancer. A 3D collagen-based scaffold model is employed here to mimic mechanical changes in normal (2 kPa, soft) versus advanced pathological (12 kPa, stiff) tissues. Activated fibroblasts grown on stiff scaffolds show lower migration and increased cell circularity compared to those on soft scaffolds. This is reflected in gene expression profiles, with cells cultured on stiff scaffolds showing upregulated DNA replication, DNA repair, and chromosome organization gene clusters, and a concomitant loss of ability to remodel and deposit ECM. Soft scaffolds can reproduce biophysically meaningful microenvironments to investigate early stage processes in wound healing and tumor niche formation, while stiff scaffolds can mimic advanced fibrotic and cancer stages. These results establish the need for tunable, affordable 3D scaffolds as platforms for aberrant stroma research and reveal the contribution of physiological and pathological microenvironment biomechanics to gene expression changes in the stromal compartment.
published_date 2022-04-01T11:25:04Z
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