Browsing by Author "Li, Zhenhua"

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    An off-the-shelf artificial cardiac patch improves cardiac repair after myocardial infarction in rats and pigs.
    (Science translational medicine, 2020-04) Huang, Ke; Ozpinar, Emily W; Su, Teng; Tang, Junnan; Shen, Deliang; Qiao, Li; Hu, Shiqi; Li, Zhenhua; Liang, Hongxia; Mathews, Kyle; Scharf, Valery; Freytes, Donald O; Cheng, Ke
    Cell therapy has been a promising strategy for cardiac repair after injury or infarction; however, low retention and engraftment of transplanted cells limit potential therapeutic efficacy. Seeding scaffold material with cells to create cardiac patches that are transplanted onto the surface of the heart can overcome these limitations. However, because patches need to be freshly prepared to maintain cell viability, long-term storage is not feasible and limits clinical applicability. Here, we developed an off-the-shelf therapeutic cardiac patch composed of a decellularized porcine myocardial extracellular matrix scaffold and synthetic cardiac stromal cells (synCSCs) generated by encapsulating secreted factors from isolated human cardiac stromal cells. This fully acellular artificial cardiac patch (artCP) maintained its potency after long-term cryopreservation. In a rat model of acute myocardial infarction, transplantation of the artCP supported cardiac recovery by reducing scarring, promoting angiomyogenesis, and boosting cardiac function. The safety and efficacy of the artCP were further confirmed in a porcine model of myocardial infarction. The artCP is a clinically feasible, easy-to-store, and cell-free alternative to myocardial repair using cell-based cardiac patches.
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    Antibody-Armed Platelets for the Regenerative Targeting of Endogenous Stem Cells.
    (Nano letters, 2019-03) Shen, Deliang; Li, Zhenhua; Hu, Shiqi; Huang, Ke; Su, Teng; Liang, Hongxia; Liu, Feiran; Cheng, Ke
    Stem cell therapies have shown promise in treating acute and chronic ischemic heart disease. However, current therapies are limited by the low retention and poor integration of injected cells in the injured tissue. Taking advantage of the natural infarct-homing ability of platelets, we engineered CD34 antibody-linked platelets (P-CD34) to capture circulating CD34-positive endogenous stem cells and direct them to the injured heart. In vitro, P-CD34 could bind to damaged aortas and capture endogenous stem cells in whole blood. In a mouse model of acute myocardial infarction, P-CD34 accumulated in the injured heart after intravenous administration, leading to a concentration of endogenous CD34 stem cells in the injured heart for effective heart repair. This represents a new technology for endogenous stem cell therapy.
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    Biomimetics: Platelet-Inspired Nanocells for Targeted Heart Repair After Ischemia/Reperfusion Injury (Adv. Funct. Mater. 4/2019)
    (Advanced Functional Materials, 2019-01) Su, Teng; Huang, Ke; Ma, Hong; Liang, Hongxia; Dinh, Phuong‐Uyen; Chen, Justin; Shen, Deliang; Allen, Tyler A; Qiao, Li; Li, Zhenhua; Hu, Shiqi; Cores, Jhon; Frame, Brianna N; Young, Ashlyn T; Yin, Qi; Liu, Jiandong; Qian, Li; Caranasos, Thomas G; Brudno, Yevgeny; Ligler, Frances S; Cheng, Ke
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    Cardiac Stromal Cell Patch Integrated with Engineered Microvessels Improves Recovery from Myocardial Infarction in Rats and Pigs.
    (ACS biomaterials science & engineering, 2020-11) Su, Teng; Huang, Ke; Mathews, Kyle G; Scharf, Valery F; Hu, Shiqi; Li, Zhenhua; Frame, Brianna N; Cores, Jhon; Dinh, Phuong-Uyen; Daniele, Michael A; Ligler, Frances S; Cheng, Ke
    The vascularized cardiac patch strategy is promising for ischemic heart repair after myocardial infarction (MI), but current fabrication processes are quite complicated. Vascularized cardiac patches that can promote concurrent restoration of both the myocardium and vasculature at the injured site in a large animal model remain elusive. The safety and therapeutic benefits of a cardiac stromal cell patch integrated with engineered biomimetic microvessels (BMVs) were determined for treating MI. By leveraging a microfluidic method employing hydrodynamic focusing, we constructed the endothelialized microvessels and then encapsulated them together with therapeutic cardiosphere-derived stromal cells (CSCs) in a fibrin gel to generate a prevascularized cardiac stromal cell patch (BMV-CSC patch). We showed that BMV-CSC patch transplantation significantly promoted cardiac function, reduced scar size, increased viable myocardial tissue, promoted neovascularization, and suppressed inflammation in rat and porcine MI models, demonstrating enhanced therapeutic efficacy compared to conventional cardiac stromal cell patches. BMV-CSC patches did not increase renal and hepatic toxicity or exhibit immunogenicity. We noted a significant increase in endogenous progenitor cell recruitment to the peri-infarct region of the porcine hearts treated with BMV-CSC patch as compared to those that received control treatments. These findings establish the BMV-CSC patch as a novel engineered-tissue therapeutic for ischemic tissue repair.
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    Dermal exosomes containing miR-218-5p promote hair regeneration by regulating β-catenin signaling.
    (Science advances, 2020-07) Hu, Shiqi; Li, Zhenhua; Lutz, Halle; Huang, Ke; Su, Teng; Cores, Jhon; Dinh, Phuong-Uyen Cao; Cheng, Ke
    The progression in the hair follicle cycle from the telogen to the anagen phase is the key to regulating hair regrowth. Dermal papilla (DP) cells support hair growth and regulate the hair cycle. However, they gradually lose key inductive properties upon culture. DP cells can partially restore their capacity to promote hair regrowth after being subjected to spheroid culture. In this study, results revealed that DP spheroids are effective at inducing the progression of the hair follicle cycle from telogen to anagen compared with just DP cell or minoxidil treatment. Because of the importance of paracrine signaling in this process, secretome and exosomes were isolated from DP cell culture, and their therapeutic efficacies were investigated. We demonstrated that miR-218-5p was notably up-regulated in DP spheroid-derived exosomes. Western blot and immunofluorescence imaging were used to demonstrate that DP spheroid-derived exosomes up-regulated β-catenin, promoting the development of hair follicles.
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    Exosome-eluting stents for vascular healing after ischaemic injury.
    (Nature biomedical engineering, 2021-10) Hu, Shiqi; Li, Zhenhua; Shen, Deliang; Zhu, Dashuai; Huang, Ke; Su, Teng; Dinh, Phuong-Uyen; Cores, Jhon; Cheng, Ke
    Drug-eluting stents implanted after ischaemic injury reduce the proliferation of endothelial cells and vascular smooth muscle cells and thus neointimal hyperplasia. However, the eluted drug also slows down the re-endothelialization process, delays arterial healing and can increase the risk of late restenosis. Here we show that stents releasing exosomes derived from mesenchymal stem cells in the presence of reactive oxygen species enhance vascular healing in rats with renal ischaemia-reperfusion injury, promoting endothelial cell tube formation and proliferation, and impairing the migration of smooth muscle cells. Compared with drug-eluting stents and bare-metal stents, the exosome-coated stents accelerated re-endothelialization and decreased in-stent restenosis 28 days after implantation. We also show that exosome-eluting stents implanted in the abdominal aorta of rats with unilateral hindlimb ischaemia regulated macrophage polarization, reduced local vascular and systemic inflammation, and promoted muscle tissue repair.
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    Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine.
    (Nature biomedical engineering, 2022-07-04) Wang, Zhenzhen; Popowski, Kristen D; Zhu, Dashuai; de Juan Abad, Blanca López; Wang, Xianyun; Liu, Mengrui; Lutz, Halle; De Naeyer, Nicole; DeMarco, C Todd; Denny, Thomas N; Dinh, Phuong-Uyen C; Li, Zhenhua; Cheng, Ke
    The first two mRNA vaccines against infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that were approved by regulators require a cold chain and were designed to elicit systemic immunity via intramuscular injection. Here we report the design and preclinical testing of an inhalable virus-like-particle as a COVID-19 vaccine that, after lyophilisation, is stable at room temperature for over three months. The vaccine consists of a recombinant SARS-CoV-2 receptor-binding domain (RBD) conjugated to lung-derived exosomes which, with respect to liposomes, enhance the retention of the RBD in both the mucus-lined respiratory airway and in lung parenchyma. In mice, the vaccine elicited RBD-specific IgG antibodies, mucosal IgA responses and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile in the animals' lungs, and cleared them of SARS-CoV-2 pseudovirus after a challenge. In hamsters, two doses of the vaccine attenuated severe pneumonia and reduced inflammatory infiltrates after a challenge with live SARS-CoV-2. Inhalable and room-temperature-stable virus-like particles may become promising vaccine candidates.
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    Hyaluronic Acid Hydrogel Integrated with Mesenchymal Stem Cell-Secretome to Treat Endometrial Injury in a Rat Model of Asherman's Syndrome.
    (Advanced healthcare materials, 2019-07) Liu, Feiran; Hu, Shiqi; Yang, Hua; Li, Zhenhua; Huang, Ke; Su, Teng; Wang, Shaowei; Cheng, Ke
    Stem cell therapies have made strides toward the efficacious treatment of injured endometrium and the prevention of intrauterine adhesions, or Asherman's syndrome (AS). Despite this progress, they are limited by their risk of tumor formation, low engraftment rates, as well as storage and transportation logistics. While attempts have been made to curb these issues, there remains a need for simple and effective solutions. A growing body of evidence supports the theory that delivering media, conditioned with mesenchymal stem cells, might be a promising alternative to live cell therapy. Mesenchymal stem cell-secretome (MSC-Sec) has a superior safety profile and can be stored without losing its regenerative properties. It is versatile enough to be added to a number of delivery vehicles that improve engraftment and control the release of the therapeutic. Thus, it holds great potential for the treatment of AS. Here, a new strategy for loading crosslinked hyaluronic acid gel (HA gel) with MSC-Sec is reported. The HA gel/MSC-Sec treatment paradigm creates a sustained release system that repairs endometrial injury in rats and promotes viable pregnancy.
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    Mesenchymal Stem Cell/Red Blood Cell-Inspired Nanoparticle Therapy in Mice with Carbon Tetrachloride-Induced Acute Liver Failure.
    (ACS nano, 2018-07) Liang, Hongxia; Huang, Ke; Su, Teng; Li, Zhenhua; Hu, Shiqi; Dinh, Phuong-Uyen; Wrona, Emily A; Shao, Chen; Qiao, Li; Vandergriff, Adam C; Hensley, M Taylor; Cores, Jhon; Allen, Tyler; Zhang, Hongyu; Zeng, Qinglei; Xing, Jiyuan; Freytes, Donald O; Shen, Deliang; Yu, Zujiang; Cheng, Ke
    Acute liver failure is a critical condition characterized by global hepatocyte death and often time needs a liver transplantation. Such treatment is largely limited by donor organ shortage. Stem cell therapy offers a promising option to patients with acute liver failure. Yet, therapeutic efficacy and feasibility are hindered by delivery route and storage instability of live cell products. We fabricated a nanoparticle that carries the beneficial regenerative factors from mesenchymal stem cells and further coated it with the membranes of red blood cells to increase blood stability. Unlike uncoated nanoparticles, these particles promote liver cell proliferation in vitro and have lower internalization by macrophage cells. After intravenous delivery, these artificial stem cell analogs are able to remain in the liver and mitigate carbon tetrachloride-induced liver failure in a mouse model, as gauged by histology and liver function test. Our technology provides an innovative and off-the-shelf strategy to treat liver failure.
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    microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential.
    (The Journal of clinical investigation, 2019-04) Qiao, Li; Hu, Shiqi; Liu, Suyun; Zhang, Hui; Ma, Hong; Huang, Ke; Li, Zhenhua; Su, Teng; Vandergriff, Adam; Tang, Junnan; Allen, Tyler; Dinh, Phuong-Uyen; Cores, Jhon; Yin, Qi; Li, Yongjun; Cheng, Ke
    Exosomes, as functional paracrine units of therapeutic cells, can partially reproduce the reparative properties of their parental cells. The constitution of exosomes, as well as their biological activity, largely depends on the cells that secrete them. We isolated exosomes from explant-derived cardiac stromal cells from patients with heart failure (FEXO) or from normal donor hearts (NEXO) and compared their regenerative activities in vitro and in vivo. Patients in the FEXO group exhibited an impaired ability to promote endothelial tube formation and cardiomyocyte proliferation in vitro. Intramyocardial injection of NEXO resulted in structural and functional improvements in a murine model of acute myocardial infarction. In contrast, FEXO therapy exacerbated cardiac function and left ventricular remodeling. microRNA array and PCR analysis revealed dysregulation of miR-21-5p in FEXO. Restoring miR-21-5p expression rescued FEXO's reparative function, whereas blunting miR-21-5p expression in NEXO diminished its therapeutic benefits. Further mechanistic studies revealed that miR-21-5p augmented Akt kinase activity through the inhibition of phosphatase and tensin homolog. Taken together, the heart failure pathological condition altered the miR cargos of cardiac-derived exosomes and impaired their regenerative activities. miR-21-5p contributes to exosome-mediated heart repair by enhancing angiogenesis and cardiomyocyte survival through the phosphatase and tensin homolog/Akt pathway.
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    Needle-Free Injection of Exosomes Derived from Human Dermal Fibroblast Spheroids Ameliorates Skin Photoaging.
    (ACS nano, 2019-10) Hu, Shiqi; Li, Zhenhua; Cores, Jhon; Huang, Ke; Su, Teng; Dinh, Phuong-Uyen; Cheng, Ke
    Human dermal fibroblasts (HDFs), the main cell population of the dermis, gradually lose their ability to produce collagen and renew intercellular matrix with aging. One clinical application for the autologous trans-dermis injection of HDFs that has been approved by the Food and Drug Administration aims to refine facial contours and slow down skin aging. However, the autologous HDFs used vary in quality according to the state of patients and due to many passages they undergo during expansion. In this study, factors and exosomes derived from three-dimensional spheroids (3D HDF-XOs) and the monolayer culture of HDFs (2D HDF-XOs) were collected and compared. 3D HDF-XOs expressed a significantly higher level of tissue inhibitor of metalloproteinases-1 (TIMP-1) and differentially expressed miRNA cargos compared with 2D HDF-XOs. Next, the efficacy of 3D HDF-XOs in inducing collagen synthesis and antiaging was demonstrated in vitro and in a nude mouse photoaging model. A needle-free injector was used to administer exosome treatments. 3D HDF-XOs caused increased procollagen type I expression and a significant decrease in MMP-1 expression, mainly through the downregulation of tumor necrosis factor-alpha (TNF-α) and the upregulation of transforming growth factor beta (TGF-β). In addition, the 3D-HDF-XOs group showed a higher level of dermal collagen deposition than bone marrow mesenchymal stem cell-derived exosomes. These results indicate that exosomes from 3D cultured HDF spheroids have anti-skin-aging properties and the potential to prevent and treat cutaneous aging.
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    Platelet membrane and stem cell exosome hybrids enhance cellular uptake and targeting to heart injury
    (Nano Today, 2021-08-01) Hu, Shiqi; Wang, Xianyun; Li, Zhenhua; Zhu, Dashuai; Cores, Jhon; Wang, Zhenzhen; Li, Junlang; Mei, Xuan; Cheng, Xiao; Su, Teng; Cheng, Ke
    Exosomes from mesenchymal stem cells have been widely studied as therapeutics to treat myocardial infarction. However, exosomes injected for therapeutic purposes face a number of challenges, including competition from endogenous exosomes, and the internalization/clearance by the mononuclear phagocyte system. There is also a lack of targeting. In this study, we hybridized stem cell-derived exosomes with platelet membranes to enhance their ability to target the injured heart and to reduce uptake by macrophages. Furthermore, we found that hybridization with platelet membranes induces macropinocytosis, enhancing the cellular uptake of exosomes by endothelial cells and cardiomyocytes drastically. In vivo studies showed the cardiac targeting ability of hybrid exosomes in a mouse model of myocardial infarction injury. Lastly, we determined cardiac functions and performed immunohistochemistry to confirm an enahnced therapeutic potency of platelet membrane modified exosomes as compared to non-modified exosomes. Our studies provide proof-of-concept data and a universal approach to enhance the binding and accumulation of exosomes in injured tissues.
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    Platelet-Inspired Nanocells for Targeted Heart Repair After Ischemia/Reperfusion Injury.
    (Advanced functional materials, 2019-01) Su, Teng; Huang, Ke; Ma, Hong; Liang, Hongxia; Dinh, Phuong-Uyen; Chen, Justin; Shen, Deliang; Allen, Tyler A; Qiao, Li; Li, Zhenhua; Hu, Shiqi; Cores, Jhon; Frame, Brianna N; Young, Ashlyn T; Yin, Qi; Liu, Jiandong; Qian, Li; Caranasos, Thomas G; Brudno, Yevgeny; Ligler, Frances S; Cheng, Ke
    Cardiovascular disease is the leading cause of mortality worldwide. While reperfusion therapy is vital for patient survival post-heart attack, it also causes further tissue injury, known as myocardial ischemia/reperfusion (I/R) injury in clinical practice. Exploring ways to attenuate I/R injury is of clinical interest for improving post-ischemic recovery. A platelet-inspired nanocell (PINC) that incorporates both prostaglandin E2 (PGE2)-modified platelet membrane and cardiac stromal cell-secreted factors to target the heart after I/R injury is introduced. By taking advantage of the natural infarct-homing ability of platelet membrane and the overexpression of PGE2 receptors (EPs) in the pathological cardiac microenvironment after I/R injury, the PINCs can achieve targeted delivery of therapeutic payload to the injured heart. Furthermore, a synergistic treatment efficacy can be achieved by PINC, which combines the paracrine mechanism of cell therapy with the PGE2/EP receptor signaling that is involved in the repair and regeneration of multiple tissues. In a mouse model of myocardial I/R injury, intravenous injection of PINCs results in augmented cardiac function and mitigated heart remodeling, which is accompanied by the increase in cycling cardiomyocytes, activation of endogenous stem/progenitor cells, and promotion of angiogenesis. This approach represents a promising therapeutic delivery platform for treating I/R injury.
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    Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair.
    (ACS nano, 2018-12) Li, Zhenhua; Shen, Deliang; Hu, Shiqi; Su, Teng; Huang, Ke; Liu, Feiran; Hou, Lei; Cheng, Ke
    Stem cell therapy is one of the promising strategies for the treatment of ischemic heart disease. However, the clinical application of stem cells transplantation is limited by low cell engraftment in the infarcted myocardium. Taking advantage of pretargeting and bioorthogonal chemistry, we engineered a pretargeting and bioorthogonal chemistry (PTBC) system to capture endogenous circulating stem cells and target them to the injured heart for effective repair. Two bioorthogonal antibodies were i.v. administrated with a pretargeting interval (48 h). Through bioorthogonal click reaction, the two antibodies are linked in vivo, engaging endogenous stem cells with circulating platelets. As a result, the platelets redirect the stem cells to the injured heart. In vitro and in vivo studies demonstrated that bioorthogonal click reaction was able to induce the conjugation of platelets and endothelial progenitor cells (EPCs) and enhance the binding of EPCs to collagen and injured blood vessels. More importantly, in a mouse model of acute myocardial infarction, the in vivo results of cardiac function, heart morphometry, and immunohistochemistry assessment all confirmed effective heart repair by the PTBC system.
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    Publisher Correction: Exosome-eluting stents for vascular healing after ischaemic injury.
    (Nature biomedical engineering, 2021-10) Hu, Shiqi; Li, Zhenhua; Shen, Deliang; Zhu, Dashuai; Huang, Ke; Su, Teng; Dinh, Phuong-Uyen; Cores, Jhon; Cheng, Ke
    The wrong Reporting Summary file was originally published for this Article; it has now been replaced with the correct file.
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    Targeted anti-IL-1β platelet microparticles for cardiac detoxing and repair.
    (Science advances, 2020-02) Li, Zhenhua; Hu, Shiqi; Huang, Ke; Su, Teng; Cores, Jhon; Cheng, Ke
    An acute myocardial infarction (AMI) induces a sterile inflammatory response that facilitates further heart injury and promotes adverse cardiac remodeling. Interleukin-1β (IL-1β) plays a central role in the sterile inflammatory response that results from AMI. Thus, IL-1β blockage is a promising strategy for treatment of AMI. However, conventional IL-1β blockers lack targeting specificity. This increases the risk of serious side effects. To address this problem herein, we fabricated platelet microparticles (PMs) armed with anti-IL-1β antibodies to neutralize IL-1β after AMI and to prevent adverse cardiac remodeling. Our results indicate that the infarct-targeting PMs could bind to the injured heart, increasing the number of anti-IL-1β antibodies therein. The anti-IL-1β platelet PMs (IL1-PMs) protect the cardiomyocytes from apoptosis by neutralizing IL-1β and decreasing IL-1β-driven caspase-3 activity. Our findings indicate that IL1-PM is a promising cardiac detoxification agent that removes cytotoxic IL-1β during AMI and induces therapeutic cardiac repair.
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    Tumor cell-derived exosomes home to their cells of origin and can be used as Trojan horses to deliver cancer drugs.
    (Theranostics, 2020-01) Qiao, Li; Hu, Shiqi; Huang, Ke; Su, Teng; Li, Zhenhua; Vandergriff, Adam; Cores, Jhon; Dinh, Phuong-Uyen; Allen, Tyler; Shen, Deliang; Liang, Hongxia; Li, Yongjun; Cheng, Ke
    Cancer is the second leading cause of death worldwide and patients are in urgent need of therapies that can effectively target cancer with minimal off-target side effects. Exosomes are extracellular nano-shuttles that facilitate intercellular communication between cells and organs. It has been established that tumor-derived exosomes contain a similar protein and lipid composition to that of the cells that secrete them, indicating that exosomes might be uniquely employed as carriers for anti-cancer therapeutics. Methods: We isolated exosomes from two cancer cell lines, then co-cultured each type of cancer cells with these two kinds of exosomes and quantified exosome. HT1080 or Hela exosomes were systemically injected to Nude mice bearing a subcutaneous HT1080 tumor to investigate their cancer-homing behavior. Moreover, cancer cell-derived exosomes were engineered to carry Doxil (a common chemotherapy drug), known as D-exo, were used to detect their target and therapeutic efficacy as anti-cancer drugs. Exosome proteome array analysis were used to reveal the mechanism underly this phenomenon. Results: Exosomes derived from cancer cells fuse preferentially with their parent cancer cells, in vitro. Systemically injected tumor-derived exosomes home to their original tumor tissues. Moreover, compared to Doxil alone, the drug-loaded exosomes showed enhanced therapeutic retention in tumor tissues and eradicated them more effectively in nude mice. Exosome proteome array analysis revealed distinct integrin expression patterns, which might shed light on the underlying mechanisms that explain the exosomal cancer-homing behavior. Conclusion: Here we demonstrate that the exosomes' ability to target the parent cancer is a phenomenon that opens up new ways to devise targeted therapies to deliver anti-tumor drugs.