Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate

Abstract

Stem cells sense and respond to the mechanical properties of the extracellular matrix. However, both the extent to which extracellular matrix mechanics affect stem cell fate in 3D micro-environments and the underlying biophysical mechanisms are unclear. We demonstrate that the commitment of mesenchymal stem cell (MSC) populations changes in response to the rigidity of 3D micro-environments, with osteogenesis occurring predominantly at 11–30 kPa. In contrast to previous 2D work, however, cell fate was not correlated with morphology. Instead, matrix stiffness regulated integrin binding as well as reorganization of adhesion ligands on the nanoscale, both of which were traction-dependent and correlated with osteogenic commitment of MSC populations. These findings suggest that cells interpret changes in the physical properties of adhesion substrates as changes in adhesion ligand presentation, and that cells themselves can be harnessed as tools to mechanically process materials into structures that feedback to manipulate their fate.

Numerical modeling of cell differentiation and proliferation in force-induced substrates via encapsulated magnetic nanoparticles

“…In this study, we have investigated how 3D force-free and forceinduced substrates affect cell proliferation and differentiation of MSCs. The results are qualitatively consistent with experimental observations [13,16,20,26,34,35,72]. We found that for a typical cell, cell internal deformation, which is developed through integrins during focal adhesions, is a key molecular mechanism in the mechanosensing process.…”

“…Once it is completely mature (MI=1), it differentiates into osteoblast within force-free and force-induced substrates after ∼7.25 days and ∼5.75 days, respectively. MSC differentiation within a substrate with a stiffness resembling that of osteogenic tissue is observed in many experimental findings [13,16,26]. MSC differentiation into osteoblast is followed by osteoblast proliferation after ∼ 14.75 and ∼ 11.75 days in forcefree and force-induced substrates, respectively.…”

“…Consequently, besides other cell reactions [38,39,41], cells may respond to changes in their mechanical environment, such as changes in matrix rigidity, by undergoing differentiation and/or proliferation [13,43]. For instance, experiments have demonstrated that for soft matrices that resembling brain tissue (0.1-1 kPa) SCs differentiate to neurogenic cells, for intermediate matrices that mimicking cartilage tissue (20-25 kPa) they differentiate into chondrogenic cells, and comparatively hard matrices that mimic the tissue of collagenous bone (30-45 kPa) they differentiate into osteogenic cells [13,26,40,55]. Although MSCs have demonstrated quicker differentiation and an increase in the proliferation rate when cultured on osteogenic substrates [40,42], mechanical forces induced into their micro-environment can actively accelerate these processes [34,35].…”

A computational model to explore the role of angiogenic impairment on endochondral ossification during fracture healing

“…We have previously used such computational models to provide support for the hypothesis that stem cell fate during fracture healing is governed by the local oxygen concentration and stiffness of the surrounding substrate (Burke and Kelly, 2012;Burke et al, 2013Burke et al, , 2014. This algorithm was developed based on in-vitro observations which demonstrate the fundamental role played by substrate stiffness in regulating MSC lineage commitment (Engler et al, 2006;Huebsch et al, 2010;Young et al, 2013;Park et al, 2011), and by experiments demonstrating that hypoxia inhibits osteogenesis and adipogenesis while promoting chondrogenesis (Kanichai et al, 2008;Cao, 2007;Hankenson et al, 2011;Peiffer et al, 2011;Hirao et al, 2006;Street et al, 2002;Gomillion and Burg, 2006;Hausman and Richardson, 2004). This computational model did not however propose a specific hypothesis for how environmental factors regulate the initiation and progression of chondrocyte hypertrophy and endochondral ossification, which is central to successful secondary fracture healing.…”

Behavior of mouse spermatogonial stem-like cells on an electrospun nanofibrillar matrix

“…The ECM is a complex structure built to meet tissue-and organ-specific requirements, which primarily consist of nanometer diameter fibrils [8]. Synthetic ECMs are often designed to exploit the interaction with cell surface receptors, which directly participate in promoting cell adhesion, migration, growth, differentiation, and apoptosis [15]. Electrospun nanofiber matrices exhibit morphological similarities to the natural ECM, as characterized by ultrafine continuous fibers, a high surface-to-volume ratio, high porosity and variable pore-size distribution [22].…”