(6ax) Engineering Materials to Recapitulate the Stem Cell Microenvironment

Despite the tremendous potential of stem cells to repair and replace damaged or diseased tissue, little progress has been made in translating stem cell-based therapies from the laboratory to the clinic. Several critical engineering challenges remain that have limited the clinical use of stem cells, including difficulties producing the large number of stem cells needed for therapeutic applications, the efficient and reproducible differentiation of stem cells into mature cell types of interest, delivery of cells to target tissues during transplantation, and maintenance of the viability and function of the cells post-transplantation. Materials science approaches stand to overcome these significant hurdles. By designing synthetic systems to mimic the native stem cell microenvironment, we can exert greater control over cell fate decisions, such as self-renewal and differentiation. I will present work from my PhD studies and postdoctoral training that employs hydrogels to identify crucial material parameters that regulate the phenotype of adult stem cells. My PhD work leveraged the modularity of protein-engineered hydrogels to develop mimics of the extracellular matrix with simultaneous tuning of stiffness, proteolytic degradability, and adhesive ligand concentration without varying other key matrix properties, such as microstructure, swelling, and nutrient transport. This system enabled me to identify matrix remodeling as a previously unrecognized requirement for maintenance of neural progenitor cell (NPC) stemness and regenerative capacity in 3D hydrogels. Whereas stiffness and adhesive ligand concentration did not alter NPC stemness, only NPCs cultured in high degradability gels maintained the capacity to self-renew as stem cells. Furthermore, matrix remodeling was necessary for efficient differentiation and maturation of NPCs into neurons and astrocytes. The precise control of material properties afforded by the ELP hydrogels permitted detailed mechanistic studies into the biochemical basis for NPC stemness maintenance regulation by matrix remodeling, revealing a cell-cell contact mediated pathway that implicated β-catenin and Yes-associated protein (YAP) signaling. Importantly, these results were generalizable to other engineered materials systems that were proteolytically or physically remodelable, suggesting that culture within remodelable 3D hydrogels is a promising strategy for expansion and differentiation of NPCs for therapeutic applications. While matrix remodeling represents a single time-dependent interaction between cells and their microenvironment, the native ECM is highly dynamic, varying its biochemical and biophysical properties during aging and disease. In my postdoc, I have developed hydrogel platforms that enable temporal control over parameters such as matrix stiffness and composition to model pathogenic processes in vitro. By mimicking changes in the muscle stem cell (MuSC) niche, I aim to uncover cell-extrinsic factors that lead to MuSC dysfunction and muscle wasting with aging and disease. Identifying target biochemical pathways that are dysregulated in the pathogenic state may enable pharmacologic interventions to restore muscle function. Overall, hydrogel-based approaches represent a significant advance in realizing the therapeutic potential of stem cells.

Teaching Interests:

Polymer Science; Thermodynamics; Mechanics of Materials; Reaction Kinetics; Biomaterials; Stem Cell Engineering; Tissue Engineering