Integrin Specificity as a Novel Strategy for Enhancing Transplanted Stem Cell Survival and Tissue Repair in Vivo

Abstract

Despite the promising clinical results for the use of human mesenchymal stem cells (hMSC) in musculoskeletal defect treatment, inadequate control of cell survival, engraftment and fate limits the success of this cell-based therapy. Integrin-mediated cell adhesion plays a central role in tissue formation, maintenance, and repair by providing anchorage forces and triggering signals that regulate cell function. We hypothesize that biomaterials presenting integrin-specific adhesive motifs will direct hMSC engraftment and function to improve bone repair. The objective of this project is to engineer bioartificial hydrogels presenting integrin-specific ligands as biomimetic cell delivery vehicles for enhanced in vivo engraftment and function – an innovative strategy as it focuses on engineering specificity to integrin receptors to promote survival and cell-based repair without the use of exogenous growth factors. We investigated the performance of a cell-mediated degradable hydrogel functionalized with integrin-specific ligands in supporting the survival of transplanted hMSC and tissue repair in a segmental bone defect. This was accomplished by incorporating the adhesive 21 integrin-specific GFOGER ligand, adhesive v3 integrin-specific RGD ligand, non-adhesive RDG peptide, or non-adhesive GAOGER peptide combined with human mesenchymal stem cells in a protease-degradable PEG-maleimide hydrogel. Cell survival was tracked through transgenic luciferase expression and bone repair was monitored by microcomputer tomography. We hypothesized that hydrogel delivery vehicles that promoted cell viability in combination with the pro-osteogenic properties of the carrier would result in superior bone repair. We found that α2β1-specific GFOGER-functionalized hydrogels promoted enhanced hMSC survival and bone repair, with differential expression of vascularization and inflammation-related genes in vivo compared to RGD- or RDG-functionalized hydrogels, highlighting integrin-specificity as an important consideration in the design of cell delivery vehicles for engraftment and tissue repair. We have generated new insights into transplanted hMSC survival, engraftment and function in a bone repair model allowing for direct correlations among hydrogel formulation and integrin specificity, transplanted cell survival, and bone repair outcomes. This work is significant and innovative because improved design of cell delivery vehicles may improve efficacy of current hMSC therapies in the clinic.