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

Amy Y Clark,Christopher T Johnson,Hannah S Theriault,Karen E Martin,José R García,Edward A Botchwey,Dennis W Zhou,Andrés J García,Woojin M Han

doi:10.1038/s41467-019-14000-9

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.

Highlights

Stem cell therapies are limited by poor cell survival and engraftment
GFOGER is a triple helical synthetic peptide derived from type I collagen with high binding affinity for α2β1 integrin[21]
Increased NuMApositive staining was evident for defects treated with GFOGERpresenting hydrogels compared with GAOGER, RGD- or RDGfunctionalized hydrogels, consistent with bioluminescence data. These results demonstrate that GFOGER-functionalized hydrogels support enhanced human bone marrow-derived mesenchymal stem cells (hMSCs) survival and persistence within bone defects compared with RGD-presenting and non-adhesive hydrogels

Summary

Introduction

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. 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. We demonstrate that hydrogels presenting integrin-specific peptides modulate hMSC activities in vitro and promote stem cell survival and engraftment within the bone defect to improve tissue repair. Integrin-specific hydrogels differentially potentiate the in vitro hMSC immunomodulatory secretome, as well as host reparative gene expression profiles in vivo These results demonstrate that biomaterial integrin specificity can be used to direct hMSC survival, engraftment, and secretory and reparative activities during tissue healing

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Conclusion