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Title: Induction of Fibrogenic Phenotype in Human Mesenchymal Stem Cells by Connective Tissue Growth Factor in a Hydrogel Model of Soft Connective Tissue
Award ID(s):
1809612
NSF-PAR ID:
10176046
Author(s) / Creator(s):
; ;
Date Published:
Journal Name:
ACS biomaterials science engineering
Volume:
5
Issue:
9
ISSN:
2373-9878
Page Range / eLocation ID:
4531-4541
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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  1. Abstract

    Dysregulation of extracellular matrix (ECM) synthesis, organization, and mechanics are hallmark features of diseases like fibrosis and cancer. However, most in vitro models fail to recapitulate the three‐dimensional (3D) multi‐scale hierarchical architecture of collagen‐rich tissues and as a result, are unable to mirror native or disease phenotypes. Herein, using primary human fibroblasts seeded into custom fabricated 3D non‐adhesive agarose molds, a novel strategy is proposed to direct the morphogenesis of engineered 3D ring‐shaped tissue constructs with tensile and histological properties that recapitulate key features of fibrous connective tissue. To characterize the shift from monodispersed cells to a highly‐aligned, collagen‐rich matrix, a multi‐modal approach integrating histology, multiphoton second‐harmonic generation, and electron microscopy is employed. Structural changes in collagen synthesis and alignment are then mapped to functional differences in tissue mechanics and total collagen content. Due to the absence of an exogenously added scaffolding material, this model enables the direct quantification of cell‐derived changes in 3D matrix synthesis, alignment, and mechanics in response to the addition or removal of relevant biomolecular perturbations. To illustrate this, the effects of nutrient composition, fetal bovine serum, rho‐kinase inhibitor, and pro‐ and anti‐fibrotic compounds on ECM synthesis, 3D collagen architecture, and mechanophenotype are quantified.

     
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