TY - JOUR
T1 - Studying Activated Fibroblast Phenotypes and Fibrosis-Linked Mechanosensing Using 3D Biomimetic Models
AU - Paradiso, Francesca
AU - Quintela, Marcos
AU - Lenna, Stefania
AU - Serpelloni, Stefano
AU - James, David
AU - Caserta, Sergio
AU - Conlan, Steve
AU - Francis, Lewis
AU - Taraballi, Francesca
N1 - Funding Information:
The authors would like to thank: Jianhua Gu, SEM AFM Core—Houston Methodist Hospital Research Institute; Matthew Vasquez, HMRI Microscopy, Advanced Cellular & Tissue Microscopy Core (ACTM) Core—Houston Methodist Research Institute; Courtney Vallien, HTL(ASCP)CMQIHCCM Comparative Medicine Pathology—Houston Methodist Research Institute. Amanda Weiskoff, Scientific Writer, Academic Affairs—Houston Methodist Academic Institute. Celtic Advanced Life Science Innovation Network, an Ireland Wales 2014–2020 program partially funded by the European Regional Development Fund through the Welsh Government.
Publisher Copyright:
© 2022 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - 3D model
KW - cancer
KW - fibrosis
KW - mechanics
KW - microenvironment
KW - stroma
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U2 - 10.1002/mabi.202100450
DO - 10.1002/mabi.202100450
M3 - Article
C2 - 35014177
AN - SCOPUS:85122965252
VL - 22
JO - Macromolecular Bioscience
JF - Macromolecular Bioscience
SN - 1616-5187
IS - 4
M1 - 2100450
ER -