Measuring dynamic cell–material interactions and remodeling during 3D human mesenchymal stem cell migration in hydrogels

Abstract

Biomaterials that mimic aspects of the extracellular matrix by presenting a 3D microenvironment that cells can locally degrade and remodel are finding increased applications as wound-healing matrices, tissue engineering scaffolds, and even substrates for stem cell expansion. In vivo, cells do not simply reside in a static microenvironment, but instead, they dynamically reengineer their surroundings. For example, cells secrete proteases that degrade extracellular components, attach to the matrix through adhesive sites, and can exert traction forces on the local matrix, causing its spatial reorganization. Although biomaterials scaffolds provide initially well-defined microenvironments for 3D culture of cells, less is known about the changes that occur over time, especially local matrix remodeling that can play an integral role in directing cell behavior. Here, we use microrheology as a quantitative tool to characterize dynamic cellular remodeling of peptide-functionalized poly(ethylene glycol) (PEG) hydrogels that degrade in response to cell-secreted matrix metalloproteinases (MMPs). This technique allows measurement of spatial changes in material properties during migration of encapsulated cells and has a sensitivity that identifies regions where cells simply adhere to the matrix, as well as the extent of local cell remodeling of the material through MMP-mediated degradation. Collectively, these microrheological measurements provide insight into microscopic, cellular manipulation of the pericellular region that gives rise to macroscopic tracks created in scaffolds by migrating cells. This quantitative and predictable information should benefit the design of improved biomaterial scaffolds for medically relevant applications.PEG-peptide hydrogels | human mesenchymal stem cells | cell migration | microrheology

Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction

“…(ii) The 3D scaffold may allow generation of mechanical force by NPCs in response to their environment (11). (iii) The 3D environment provides a high surface area for growth and migration (35), which can be tuned to support other cell behaviors, such as differentiation or maturation. In vivo-like cell−cell interactions may lead to more realistic gene expression and cellular behavior.…”

Mesenchymal stromal cell remodeling of a gelatin hydrogel microenvironment defines an artificial hematopoietic stem cell niche

“…While we observed significant matrix remodeling via repeated compressive testing in High hydrogels seeded with the highest MSC density, no clear trends were observed in the Low or Med conditions. Recent results from Schultz et al described non-uniform matrix remodeling [93] as a result of differences in diffusive path lengths and reaction times for MMPs vs. TIMPs. This suggests remodeling of our hydrogels was likely non-uniform, making it difficult to resolve local remodeling processes within the heterotypic HSC-MSC cultures.…”

Isolation and Identification of Proteins Secreted by Cells Cultured within Synthetic Hydrogel-Based Matrices

“…This particular composition was selected because of frequent and broad use of RGDS for promoting the adhesion and survival of cells within synthetic matrices and the previous observation of cell spreading over days within this matrix density, suggesting some degree of cell-driven remodeling of the initial matrix. 17 With this approach now established, the effects of different peptides or matrix densities and moduli on the profile of secreted proteins may be examined in future studies. Further, if an alternative synthetic matrix is used, materials for cell encapsulation should be prepared per standard procedures for that system.…”