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

• Published in: Macromolecular bioscience Vol. 22; no. 4; pp. e2100450 - n/a
• Main Authors: Paradiso, Francesca, Quintela, Marcos, Lenna, Stefania, Serpelloni, Stefano, James, David, Caserta, Sergio, Conlan, Steve, Francis, Lewis, Taraballi, Francesca
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.04.2022
• Subjects: 3D model; Biomechanics; Biomimetics; Cancer; Cell migration; Chromosomes; Collagen; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA repair; Extracellular matrix; Extracellular Matrix - metabolism; Fibroblasts; Fibrosis; Gene clusters; Gene expression; Humans; mechanics; microenvironment; Microenvironments; Neoplasms - genetics; Neoplasms - metabolism; Phenotype; Phenotypes; Scaffolds; Scars; Solid tumors; Stroma; Three dimensional models; Tissue Scaffolds; Tumor Microenvironment; Tumors; Wound healing; microenvironment; 3D model; cancer; fibrosis; mechanics; stroma
• ISSN: 1616-5187; 1616-5195
• DOI: 10.1002/mabi.202100450

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. A 3D collagen‐based scaffold model is employed to mimic mechanical changes in normal (2 kPa, soft) versus advanced pathological (12 kPa, stiff) tissues and investigate normal/activated fibroblasts phenotype, migration, gene expression profile in response to microenvironment changes in stiffness. These results reveal the contribution of physiological and pathological microenvironment biomechanics to gene expression changes in the stromal compartment.