Integrin-specific hydrogels modulate transplanted human bone marrow-derived mesenchymal stem cell survival, engraftment, and reparative activities

Abstract

Stem cell therapies are limited by poor cell survival and engraftment. A hurdle to the use of materials for cell delivery is the lack of understanding of material properties that govern transplanted stem cell functionality. Here, we show that synthetic hydrogels presenting integrin-specific peptides enhance the survival, persistence, and osteo-reparative functions of human bone marrow-derived mesenchymal stem cells (hMSCs) transplanted in murine bone defects. Integrin-specific hydrogels regulate hMSC adhesion, paracrine signaling, and osteoblastic differentiation in vitro. Hydrogels presenting GFOGER, a peptide targeting α2β1 integrin, prolong hMSC survival and engraftment in a segmental bone defect and result in improved bone repair compared to other peptides. Integrin-specific hydrogels have diverse pleiotropic effects on hMSC reparative activities, modulating in vitro cytokine secretion and in vivo gene expression for effectors associated with inflammation, vascularization, and bone formation. These results demonstrate that integrin-specific hydrogels improve tissue healing by directing hMSC survival, engraftment, and reparative activities.

Shattering barriers toward clinically meaningful MSC therapies

“…The best formulations showed more than twofold increases in cell proliferation on day 14 and up to threefold higher mRNA expression of relevant factors, such as angiopoietin and fibroblast growth factor-2, compared to formulations without the thermoresponsive polymer. Along with tuning mechanical properties, synthetic hydrogels with added linker molecules, including activated peptides and pro-inflammatory cytokines like IFN-γ, have also been explored as a technique to enhance MSC survival, persistence at the target site, and cytokine secretion ( 118 , 119 ). For example, hydrogels engineered with the adhesive integrin-specific peptide GFOGER compared to the nonadhesive peptide GAOGER have been shown to significantly enhance the in vitro secretion of relevant cytokines, such as IL-8 and VEGF, and subsequently enhance MSC survival, engraftment, and bone repair in an in vivo mouse bone defect model ( 118 ).…”

Hydrogel as a Biomaterial for Bone Tissue Engineering: A Review

“…The influence of biomaterials on bone regeneration is mainly through the interaction between cells and surrounding biomaterials, in which interactions of cells play a main role in determining the behavior of cells on the surface of biomaterials [ 17 ]. Integrin is a heterodimeric receptor in the cell membrane, which acts as a linker between cells and substrates by binding to adhesion proteins on the surface of biological materials [ 18 ]. It is the key determinant of the subsequent cell activity including cell morphology, migration, proliferation, and differentiation.…”

Engineered Collagen Matrices

“…For example, DGEA was bound to alginate using carbodiimide chemistry and found to enhance osteogenic differentiation of mesenchymal stem cells [ 146 ]. Incorporation of GFOGER into scaffolds made from multi-arm PEG-maleimide has similarly shown that it can improve osteogenic outcomes, including the enhancement of bone repair in vivo [ 147 ]. The application of GFOGER-modified materials is not limited to bone, as such materials have also been found to support the culture and function of intestinal enteroids and endometrial spheroids [ 148 ] or mimic the tumor microenvironment [ 149 ], amongst other applications.…”