Substrate stiffness and oxygen availability as regulators of mesenchymal stem cell differentiation within a...

Mechanical stimuli such as tissue deformation and fluid flow are often implicated as regulators of mesenchymal stem cell (MSC) differentiation during regenerative events in vivo. However, in vitro studies have identified several other physical and biochemical environmental cues, such as substrate stiffness and oxygen availability, as key regulators of stem cell fate. Hypotheses for how MSC differentiation is regulated in vivo can be either corroborated or rejected based on the ability of in silico models to accurately predict spatial and temporal patterns of tissue differentiation observed experimentally. The goal of this study was to employ a previously developed computational framework to test the hypothesis that substrate stiffness and oxygen availability regulate stem cell differentiation during tissue regeneration within an implanted bone chamber. To enable a prediction of the oxygen levels within the bone chamber, a lattice model of angiogenesis was implemented where blood vessel progression was dependent on the local mechanical environment. The model successfully predicted key aspects of MSC differentiation, including the correct spatial development of bone, marrow and fibrous tissue within the unloaded bone chamber. The model also successfully predicted chondrogenesis within the chamber upon the application of mechanical loading. This study provides further support for the hypothesis that substrate stiffness and oxygen availability regulate stem cell differentiation in vivo. These simulations also highlight the indirect role that mechanics may play in regulating MSC fate by inhibiting blood vessel progression and hence disrupting oxygen availability within regenerating tissues.