Hydrogel engineering for enhancing vascularization and augmenting immunomodulation of encapsulated mesenchymal stem cells
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Since the discovery of adult human mesenchymal stem cells in the late 1900’s, the potential of utilizing these cells in the clinic for cell-therapy applications has been an ever-present goal. Unfortunately, clinical trials using these cells have garnered lackluster results with a high degree of variability in patient outcome and in many cases no difference between patients who received these adult stem cell or placebo. Various factors account for such results including the inability to properly control cell presence via the routine method of intravenous administration, the inability to control cell phenotype once the cells are injected into the patient and the harsh microenvironment cells are injected into. Biomaterials can provide solutions for these factors through engineering scaffolds to present needed signals to both encapsulated stem cells and the surrounding microenvironment. The objective of this project is to engineer bioartificial hydrogels presenting specific signals in the form of integrin-specific ligands and covalently-bound proteins to enhance mesenchymal stem cell activity and efficacy in wound and disease models. We investigated the application of these bioarticifial hydrogels towards two different goals: 1) to enhance vascularization and associated stem cell survival in a critical size bone defect and 2) to enhance immunomodulation of stem cells in a wound regeneration model. For our first goal, we found that hydrogels presenting the α2β1 ligand ‘GFOGER’ resulted in enhanced vascularization of bone defects compared to hydrogels presenting the αvβ3 ligand ‘RGD’ in the absence of vasculogenic protein. For our second goal, we found that hydrogels functionalized tethered IFN-γ enhanced the immunomodulatory properties of encapsulated hMSCs which led to enhanced tissue resolution in a colonic wound model. Together, our findings elucidate novel ways to enhance adult stem cell efficacy and further the applicability of these cells in clinical settings.