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

Abstract

The lower cell survival and retention in the hostile microenvironment after transplantation has been implicated 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. The mesenchymal stem cells (MSCs) were harvested from male rats and cytoprotective effect of this designer SAP (DSAP) on cultured MSCs was detected by Hoechst 33342 staining after being exposed to oxygen and glucose deprivation (OGD). The cytoprotective effect of MSCs seeded in DSAP (DSAP‐MSCs) on OGD treated cardiomyocytes was examined by TUNEL staining, phosphorylated (p‐) protein kinase B (Akt) level, and ELISA. The therapeutic potential of MSC transplantation carried in DSAP was evaluated in a female rat MI model. PBS, MSCs alone, MSCs seeded in SAP (SAP‐MSCs), or DSAP‐MSCs were transplanted into the border of the infarcted area, respectively. DSAP not only increased the proliferation of MSCs and decreased apoptosis of MSCs after OGD treatment but also promoted the secretion of IGF‐1 and HGF in MSCs. Treatment with culture supernatant of DSAP‐MSCs markedly reduced the percentage of apoptotic cardiomyocytes and increased the level of p‐Akt. Compared with the MSC group and SAP‐MSC group, DSAP‐MSC injection improved cardiac function and reduced infarct size, collagen content, and cell apoptosis. The number of Y chromosome–positive cells and microvessels in the DSAP‐MSC group was higher than those in the MSC group and SAP‐MSC group. Moreover, DSAP‐MSC transplantation down‐regulated the expression of IL‐6 and IL‐1β and up‐regulated the level of VEGF and HGF. Interestingly, miR‐21 was enriched in DSAP‐MSC‐derived exosomes (DSAP‐MSC‐Exos) and the protection against cardiomyocyte apoptosis by DSAP‐MSC‐Exos was inhibited when miR‐21 was knocked down. Furthermore, miR‐21 contributed to the improvement of cardiac function after DSAP‐MSC‐Exo injection in a rat model of MI. Additionally, the combination of DSAP and cardiotrophin‐1 (Ctf1) pretreatment further improved the survival of MSCs and the efficiency of MSC transplantation. We proposed QHREDGS‐modified SAP as an effective cell delivery system and demonstrated that MSC transplantation in this DSAP promoted angiogenesis and paracrine, thereby reducing scar size and cell apoptosis as well as improving cardiac function probably via exosome‐mediated miR‐21 after MI. Furthermore, for the first time, we proposed that DSAP, especially working together with Ctf1 pretreatment, could be a valuable way to improve the survival of MSCs and the efficiency of MSC transplantation after MI.—Cai, H., Wu, F.‐Y., Wang, Q.‐L., Xu, P., Mou, F.‐F., Shao, S.‐J., Luo, Z.‐R., Zhu, J., Xuan, S.‐S., Lu, R., Guo, H.‐D. Self‐assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction. FASEB J. 33, 8306–8320 (2019). http://www.fasebj.org

Designer Self‐Assembling Peptide Hydrogels to Engineer 3D Cell Microenvironments for Cell Constructs Formation and Precise Oncology Remodeling in Ovarian Cancer

“…The advantage of this molecular building block, compared with other self‐assembling peptides (Table 2), is its similarity to the RGD (arginine–glycine–aspartic acid residues) tripeptide, a sequence within fibronectin that favors cell attachment or archorage. It has excellent regenerative potential as fillers or scaffolds for a variety of tissue and organ, [ 9b ] especially in human neural growth regeneration, [ 67 ] mesenchymal stem cell transplantation, [ 84 ] and cardiac cell transplantation therapy for fibrotic tissue remodeling. [ 85 ] Compared to intramyocardial MSC injection in rat, more cardiac functionality, greater initial retention and survival of donor mesenchymal stem cells (MSCs) are observed in the epicardium with the instantly‐produced PuraMatrix hydrogel incorporating MSCs (epicardial PM‐MSC therapy), by which a group of tissue repair‐related genes are upregulated.…”

“…Based on the molecular self‐assembly in PuraMatrix hydrogel, the peptide motif QHREDGS derived from angiopoeitin‐1 is tethered to RADA16‐I peptide. [ 84 ] When carried the MSCs in hydrogel and transplanted into the border of the infarcted cardiac area, the functionalized PuraMatrix hydrogel increases the proliferation of MSCs and decreases apoptosis of MSCs and in situ promote angiogenesis and paracrine by the secretion of IGF‐1 and HGF in rat models. Except of topographic benefits and diverse peptide backbones in RADA16‐I peptide and derivatives, many functional motifs are yet tethered to C‐terminus or N‐terminus of peptide backbone to improve molecular building blocks and accurately mimic the ECM features in vivo.…”

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…Increasing evidence has indicated that the EV microRNA (miRNA) content as one of their most likely paracrine mechanism(s) of action. Several miRNAs have been associated with MSC-EV cardioprotective, pro-survival and angiogenic effects, including, for example, miR-21 [187]; miR-125b [188]; miR-320d [189]; miR-95-3p [190]; miR-210 [191]; miR-29 and miR-24 [180]. Additionally, EVs have been shown to biochemically restore ATP and NADH levels and redox state within the injured tissue [192].…”

A Cell-Free SDKP-Conjugated Self-Assembling Peptide Hydrogel Sufficient for Improvement of Myocardial Infarction

“…After injection of RADA16-II into the infarcted myocardium, the empty space of the hydrogel was cellularized by endothelial, smooth muscle, and cardiac cells within days, which showed the cell recruitment potential of the RADA-based hydrogels for endogenous regeneration of infarcted myocardium [30,55]. In order to improve cardiac function, cardioprotective and angiogenic cues such as IGF1 [56], PDGF [54], VEGF [57], FGF [58], Notch1 [16], and QHREDGS [59] have been integrated with the SAP hydrogels.…”