Self-assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction

The lower cell survival and retention in the hostile microenvironment after transplantation has been im- plicated as a major bottleneck in the advancement of stem cell therapy for myocardial infarction (MI). In this study, we designed a novel self-assembling peptide (SAP) by attaching prosurvival peptide QHREDGS derived from angiopoeitin-1 to the known SAP,RADA16-I. Themesenchymal stem cells (MSCs) were harvested frommale rats and cytoprotective effect of this designerSAP(DSAP)onculturedMSCswas detectedbyHoechst 33342 staining afterbeing exposed to oxygen andglucosedeprivation (OGD).The cytoprotective effect ofMSCseeded inDSAP(DSAP-MSC)on OGDtreated cardiomyocytes was examined byTUNELstaining, phosphorylated (p-) protein kinase B(Akt) level, and ELISA.Thetherapeutic potentialofMSCtransplantation carried inDSAPwasevaluated in afemaleratMI model. PBS, MSC alone,MSC seeded in SAP (SAP-MSC), or DSAP-MSC were transplanted into the border of the infarcted area, respectively.DSAPnotonlyincreasedtheproliferationofMSCsanddecreasedapoptosis ofMSCsafterOGDtreatment but also promoted the secretion of IGF-1 and HGF in MSCs. Treatment with culture supernatant of DSAP-MSC markedlyreducedthepercentageofapoptoticcardiomyocytesandincreasedthelevelofp-Akt.ComparedwiththeMSC groupandSAP-MSCgroup,DSAP-MSCinjection improvedcardiac functionandreducedinfarct size, collagen content, and cell apoptosis.The number ofYchromosome–positive cells andmicrovessels in theDSAP-MSCgroupwashigher than those in the MSC group and SAP-MSC group. Moreover, DSAP-MSC transplantation down-regulated the ex- pression of IL-6 and IL-1b and up-regulated the level ofVEGF and HGF. Interestingly, miR-21 was enriched inDSAP- MSC–derived exosomes (DSAP-MSC-Exo) and the protection against cardiomyocytes apoptosis by DSAP-MSC-Exo was inhibited when miR-21 was knocked down. Furthermore, miR-21 contributed to the improvement of cardiac functionafterDSAP-MSC-Exoinjection inaratmodelofMI.Additionally,thecombinationofDSAPandcardiotrophin- 1 (Ctf1) pretreatment further improved the survival of MSC and the efficiency of MSC transplantation.We proposed QHREDGS-modifiedSAPasaneffective celldelivery systemanddemonstratedthatMSCtransplantation inthisDSAP promotedangiogenesisandparacrine,therebyreducingscarsizeandcellapoptosisaswellasimprovingcardiacfunction probably via exosome-mediatedmiR-21 after MI. Furthermore, for the first time, we proposed that DSAP, especially working together with Ctf1 pretreatment, could be a valuableway to improve the survival ofMSCandthe efficiency of MSCtransplantation after MI.