Targeted repair of heart injury by stem cells fused with platelet nanovesicles

Tang, Junnan; Su, Teng; Dinh, Phuong; Wang, Zegen; Vandergriff, Adam C.; Hensley, Michael Taylor; Cores, Jhon; Allen, Tyler A.; Li, Tao‐Sheng; Sproul, Erin P.; Mihalko, Emily; Lobo, Leonard J.; Ruterbories, Laura; Lynch, Alex; Brown, Ashley; Caranasos, Thomas G.; Shen, Deliang; Stouffer, George A.; Gu, Zhen; Zhang, Jinying

doi:10.1038/s41551-017-0182-x

Cited by 189 publications

(176 citation statements)

References 34 publications

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“…Due to their high specificity, antibodies and antibody fragments have been the targeting molecule of choice [75]. Recent studies also showed that platelet membranes could be utilized to target cells to the infarct heart [76]. Recent developments in phage display have yielded many new targeting molecules such as the CHP [26,27].…”

Section: Discussionmentioning

confidence: 99%

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

et al. 2018

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Rationale: Cardiac stem cell-derived exosomes have been demonstrated to promote cardiac regeneration following myocardial infarction in preclinical studies. Recent studies have used intramyocardial injection in order to concentrate exosomes in the infarct. Though effective in a research setting, this method is not clinically appealing due to its invasive nature. We propose the use of a targeting peptide, cardiac homing peptide (CHP), to target intravenously-infused exosomes to the infarcted heart.Methods: Exosomes were conjugated with CHP through a DOPE-NHS linker. Ex vivo targeting was analyzed by incubating organ sections with the CHP exosomes and analyzing with fluorescence microscopy. In vitro assays were performed on neonatal rat cardiomyocytes and H9C2 cells. For the animal study, we utilized an ischemia/reperfusion rat model. Animals were treated with either saline, scramble peptide exosomes, or CHP exosomes 24 h after surgery. Echocardiography was performed 4 h after surgery and 21 d after surgery. At 21 d, animals were sacrificed, and organs were collected for analysis.Results: By conjugating the exosomes with CHP, we demonstrate increased retention of the exosomes within heart sections ex vivo and in vitro with neonatal rat cardiomyocytes. In vitro studies showed improved viability, reduced apoptosis and increased exosome uptake when using CHP-XOs. Using an animal model of ischemia/reperfusion injury, we measured the heart function, infarct size, cellular proliferation, and angiogenesis, with improved outcomes with the CHP exosomes.Conclusions: Our results demonstrate a novel method for increasing delivery of for treatment of myocardial infarction. By targeting exosomes to the infarcted heart, there was a significant improvement in outcomes with reduced fibrosis and scar size, and increased cellular proliferation and angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

et al. 2018

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“…Several types of biomarkers have been shown to be overexpressed in diseased cardiovascular regions, which have been identified as targets for nanomedicine. Thus, ligand‐installed nanocarriers are now being investigated for their ability to target cardiovascular diseases, for instance, atherosclerosis, myocardial infarction, and heart injury ( Table 5 ).…”

Section: Targeting Strategies With Ligand‐installed Nanocarriersmentioning

confidence: 99%

Ligand‐Installed Nanocarriers toward Precision Therapy

2019

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Development of drug‐delivery systems that selectively target neoplastic cells has been a major goal of nanomedicine. One major strategy for achieving this milestone is to install ligands on the surface of nanocarriers to enhance delivery to target tissues, as well as to enhance internalization of nanocarriers by target cells, which improves accuracy, efficacy, and ultimately enhances patient outcomes. Herein, recent advances regarding the development of ligand‐installed nanocarriers are introduced and the effect of their design on biological performance is discussed. Besides academic achievements, progress on ligand‐installed nanocarriers in clinical trials is presented, along with the challenges faced by these formulations. Lastly, the future perspectives of ligand‐installed nanocarriers are discussed, with particular emphasis on their potential for emerging precision therapies.

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“…The exact numbers of cells in myocardium was quantified by Y chromosome‐specific PCR. Quantitative PCR for the Sex‐determining Region Y gene (SRY) was performed at 1 day (after fluorescence imaging), 7 days, and 2 weeks after cell transplantation . The primers sequences for specific Y chromosome of rat were as follows: sense: 5′‐GAG CTT TGG GAG CAG TGA C‐3′, antisense: 5′‐ATG AGG CTG ATA TTT ATA GTT TGG‐3′.…”

Section: Methodsmentioning

confidence: 99%

“…Stem cell‐based regenerative therapy has not fulfilled decade's long expectations as a promising treatment for acute myocardial infarction (MI) and heart failure . The underlying reasons for the unsatisfactory results in clinical trials are complicated and not fully clarified; however, poor cell homing, retention, and engraftment are generally regarded as major obstacles to achieving a significant functional benefit .…”

Section: Introductionmentioning

confidence: 99%

Modification with CREKA Improves Cell Retention in a Rat Model of Myocardial Ischemia Reperfusion

et al. 2019

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Poor cell homing limits the efficacy of cardiac cellular therapy. The homing peptide, cysteinearginine-glutamic acid-lysine-alanine (CREKA), targets fibrin effectively which is involved in the repair process of tissue injury. Here, we assessed if CREKA-modified stem cells had enhanced fibrin-mediated homing ability resulting in better functional recovery and structural preservation in a rat myocardial injury model. CREKA-modified mesenchymal stem cells (CREKA-MSCs) were obtained via membrane fusion with CREKA-modified liposomes. The fibrin targeting ability of CREKA-MSCs was examined both in vitro and in vivo. Under both static and flow conditions in vitro, CREKA significantly enhanced MSCs binding ability to fibrin clots (2.6-and 2.3-fold, respectively). CREKA-MSCs showed 6.5-fold higher accumulation than unmodified MSCs in injured rat myocardium one day after administration, resulting in better structural preservation and functional recovery. Fibrin is, therefore, a novel target for enhancing homing of transplanted cells to injured myocardium, and the delivery system of fibrin-targeting is on behalf of a universalizable platform technology for regenerative medicine. STEM CELLS 2019;37:663-676 SIGNIFICANCE STATEMENTPoor cell homing limits the efficacy of cardiac cellular therapy. Fibrin expression after myocardial injury renders fibrin, an ideal target for the delivery of stem cells. In this study, the authors developed fibrin-targeting stem cells for the repair of myocardial injury using cysteine-arginineglutamic acid-lysine-alanine (CREKA) as the targeting moiety. CREKA-modified mesenchymal stem cells (MSCs) exhibited potent fibrin-targeting ability both in vitro and in vivo, highlighting the utility of active fibrin targeting in cardiac cellular therapy.

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Targeted repair of heart injury by stem cells fused with platelet nanovesicles

Cited by 189 publications

References 34 publications

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

Ligand‐Installed Nanocarriers toward Precision Therapy

Modification with CREKA Improves Cell Retention in a Rat Model of Myocardial Ischemia Reperfusion

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