SUN-027 Delivery of MSCs with a Hybrid β-sheet Peptide Hydrogel Consisting IGF-1C Domain and D-form Peptide for Acute Kidney Injury Therapy

Abstract

By providing an appropriate microenvironment, synthetic biomaterials have been progressively successful in stem cell-based tissue regeneration by enhancing the engraftment and survival of transplanted cells. The designs with bioactive motifs to influence cell behavior and with D-form amino acid to modulate scaffold stability will be critical for the development and optimization of self-assembling biomimetic hydrogel scaffolds for stem cell therapy. In this study, we linked naphthalene (Nap) covalently conjugated a short D-form peptide (Nap-DFDFG) to C domain of insulin-like growth factor-1 (IGF-1C) as a functional peptide-based scaffold. Our purpose is to provide a functional self-assembling peptide hydrogel with encapsulated human placenta derived mesenchymal stem cells (hP-MSCs) and thereby to enhance the therapeutic efficiency of hP-MSCs in murine acute kidney injury (AKI) model. Our results revealed that a typical β-sheet conformation was confirmed and this self-assembling peptide hydrogel exhibited higher affinity with IGF-1 receptor. Furthermore, this hydrogel could provide a favorable niche for hP-MSCs and thereby ameliorate renal function in an AKI model by promoting cell survival and angiogenesis. In conclusion, by covalently linking the desired functional group to D-form peptide to create a functional hydrogel, this self-assembling β-sheet peptide hydrogel will serve as a promising platform for future tissue-engineering and stem cell therapy. We prepared a supramolecular self-assembly peptide Nap-DFDFG-IGF-1C by standard solid phase peptide synthesis (SPPS), and profiled the characteristics by circular dichroism (CD) analysis, surface plasmon resonance (SPR), transmission electron microscope (TEM) and rheological analysis. For real-time tracing the cell fate post transplantation, we introduced dual fusion MSCs which express firefly luciferase and GFP simultaneously. Also we utilized the bioluminescence imaging (BLI) to longitudinally monitor the dynamics of cell retention and renal angiogenesis. Serial experiments have bee done to evaluate the putative therapeutic effect for AKI. We here reported a hybrid self-assembly peptide Nap-DFDFG-IGF-1C. CD analysis revealed the peptide was constrained to a typical β-sheet conformation via a heating-cooling pathway, leading to an enhanced affinity with recombinant human IGF-1 receptor (rhIGF-1R) comfirmed by SPR. A cross-linked nanofibrous structure was observed by TEM and the rheological analysis evidenced its hydrogel property. Our BLI results showed that delivery of MSCs with the IGF-1C hydrogel contribute to an enhanced cell retention and renal angiogenesis, which rsulted in repair and regeneration post AKI. In summary, we reported a cell enhancement strategy with a hybrid β-sheet peptide hydrogel which holds bioactive motif IGF-1C as functional backbone for the first time. This hydrogel favors cell retention, provides a pro-angiogenesis niche for the transplanted cells, and thereby restored the renal architecture and function post AKI. This study introduced a brand-new strategy for integration of self-assembly peptide and stem cell therapy and might shed light into the development of tissue engineering as well as regeneration medicine.