Enhancing the Potency of Growth Factor-Mimicking Peptides via Cross-Presentation With Integrin Ligands
Abstract
Growth factors enhance survival and integration of transplanted Mesenchymal Stromal Cells (MSC), but successful supplementation often requires supraphysiological growth factor doses, risking off-target effects. Short peptide mimics like the knuckle epitope (KE) of Bone Morphogenetic Protein 2 (BMP-2) can be covalently immobilized to biomaterials, localizing bioactivity at the delivery site. However, these short peptides often lack the potency of full-length growth factors. We sought to improve the potency of alginate-grafted KE to encourage MSC osteogenic differentiation. When alginate gels co-presented KE and integrin-binding cyclo-RGD (cRGD) peptides, MSC expressed early markers of osteogenesis (Runt-related Transcription Factor2, RUNX2, Alkaline Phosphatase, ALP, and osteocalcin, OCN) in a KE-dose dependent manner. When co-presented with cRGD, high concentrations of KE partially mimicked the osteogenic potential (ALP induction) of full-length BMP-2. Proximity between KE and cRGD may be the mechanism through which high dose KE induces osteogenesis in the presence of cRGD. To investigate this possibility, we used orthogonal strain-promoted azide-alkyne cycloaddition (SPAAC) and maleimide-thiol chemistries to graft KE and cRGD in a bivalent (same alginate chain) and a monovalent (different alginate chain) manner, at constant bulk peptide concentration. Bivalent presentation of peptides (separation distance of 5.5 ± 0.5 nm verified by FRET) ultimately increased RUNX2 and ALP…
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