Stiffness Gradients Mimicking In Vivo Tissue Variation Regulate Mesenchymal Stem Cell Fate

Abstract

Mesenchymal stem cell (MSC) differentiation is regulated in part by tissue stiffness, yet MSCs can often encounter stiffness gradients within tissues caused by pathological, e.g., myocardial infarction ∼8.7±1.5 kPa/mm, or normal tissue variation, e.g., myocardium ∼0.6±0.9 kPa/mm; since migration predominantly occurs through physiological rather than pathological gradients, it is not clear whether MSC differentiate or migrate first. MSCs cultured up to 21 days on a hydrogel containing a physiological gradient of 1.0±0.1 kPa/mm undergo directed migration, or durotaxis, up stiffness gradients rather than remain stationary. Temporal assessment of morphology and differentiation markers indicates that MSCs migrate to stiffer matrix and then differentiate into a more contractile myogenic phenotype. In those cells migrating from soft to stiff regions however, phenotype is not completely determined by the stiff hydrogel as some cells retain expression of a neural marker. These data may indicate that stiffness variation, not just stiffness alone, can be an important regulator of MSC behavior.

Addition of hyaluronic acid improves cellular infiltration and promotes early-stage chondrogenesis in a collagen-based scaffold for cartilage tissue engineering

“…From a TE perspective, improving the mechanical properties of scaffolds is beneficial especially for their performance in vivo. The mechanical properties of a substrate or scaffold have been shown to affect the fate of MSCs in vitro (Discher et al, 2005, Karamichos et al, 2008, Vickers et al, 2010, Tse and Engler, 2011. Given that no significant differences were observed as a result of the incorporation of the two different GAG types, it is likely that any differences in MSC response observed during the in vitro culture were not strongly influenced by the mechanical properties of the scaffolds but were due to differences in composition and scaffold architecture.…”

Rapid Fabrication of Living Tissue Models by Collagen Plastic Compression: Understanding Three-Dimensional Cell Matrix Repair In Vitro

“…Other groups have suggested that cell behavior is more biomimetic when cells are cultured in stiffer matrices, in the case of stem cell differentiation, relating cell fate to the stiffness of the parent tissues, varying from brain (to neurites) at the soft end to bone (to osteoblasts) at the hard extreme. 10 Cell-generated tensional homeostasis is also a critical factor in cell responses, so the mechanical environment in which a cell resides, and then the cell response to this mechanical environment in terms of endogenous tension generation, greatly influences cell behavior. 11 Perhaps, the simplest hypothesis to explain duro-taxis, is one based on the mechanics, as opposed to one based on the biology.…”

Controlled Assembly of Fibronectin Nanofibrils Triggered by Random Copolymer Chemistry

“…Adhesion, migration and differentiation processes are dependent of both surface chemistry and stiffness [37][38][39] in addition to the surface topography and wettability. 40 Cells have an ability to sense and probe the stiffness of their surroundings as they adhere to and interact with the local ECM.…”