A microparticle engineering approach to enhance the potency of mesenchymal stem cells

Abstract

Cell-based therapies, which rely on transplanted cells to restore function to damaged tissues, are currently under investigation in clinical trials. Stem and progenitor cells, including mesenchymal stem cells (MSCs), have shown potential in pre-clinical models to treat diseases ranging from connective tissue defects, through differentiating into bone or cartilage forming cells, to inflammatory conditions, through suppressing activated immune cells. While the ability of stem cells to differentiate into multiple lineages, secrete trophic factors, and modulate inflammatory processes has made them applicable to many diseases, these diverse functions also pose challenges in controlling their phenotype. In this thesis a new platform technology to influence the phenotype of cells is described and used to solve three critical challenges in MSCbased therapies, controlling MSC differentiation, tracking cells, and enhancing MSC's immunomodulatory potency. MSCs were found to efficiently and stably internalize micron-sized biodegradable particles. The platform can be tuned to specific applications through incorporation of phenotype altering drugs or other payloads into particles. In the first study, particles were loaded with a small molecule drug, dexamethasone (DEX), that induces MSC osteogenic differentiation. Modification of MSCs with DEX-particles resulted in differentiation of particle-laden cells to the same extent as those grown in osteogenic media. Furthermore, DEX was released from the cells in sufficient quantities to influence neighboring and distant cells demonstrating the particle platform can influence both the modified cell and its microenvironment. Next, the platform was adapted to address the need for longitudinal tracking of MSCs. Loading iron oxide nanoparticles in the microparticles resulted in enhanced tracking of MSCs by MRI from 6 days with nanoparticles alone to beyond 12 days with iron oxide microparticles. Finally, the novel discovery that glucocorticoid steroids significantly increase the immunomodulatory potency of MSCs by up-regulating expression of indoleamine-2,3- dioxygenase (IDO) is reported. Loading MSCs with particles containing the glucocorticoid steroid, budesonide, doubled their potency in suppressing activated peripheral blood mononuclear cell co-cultures in an IDO dependent manner. While the platform presented here was used to control, track, and augment MSCs, it can easily be tailored to control the function of other therapeutically relevant cells to develop next-generation cell-based therapies.