Stem Cell Fate Within 3D Hydrogels is Mediated by Network Structure-Dependent Traction Generation

A continuing goal in biomaterials research is to understand how cell adhesion to the surrounding materials and/or matrix regulates cell behavior in 3D. Advanced understanding of these processes may aid the development of synthetic biomaterials for tissue engineering applications, as well as to help understand basic cellular processes. The majority of past work, however, has focused on cell behavior atop 2D substrates that poorly recapitulate the 3D in vivo microenvironment [1]. Recent reports have suggested that within 3D hydrogels, encapsulated human mesenchymal stem cell (hMSC) fate is not determined by cell morphology or matrix mechanics alone [2], but by gel-structure dependent traction force generation [3]. As hMSCs represent a promising cell source for regenerative applications [4], it is critical to better develop our understanding of the link between cell fate and microenvironmental physical and biochemical cues in 3D, with a focus on the range of materials used in regenerative medicine. In the current work, hMSCs were encapsulated within degradable and non-degradable hyaluronic acid (HA) hydrogels of similar elastic moduli to assess the influence of hydrogel remodeling and cellular traction generation on differentiation lineage specification.