Browsing by Author "Tang, Junnan"

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Open Access
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.
Open Access
Cardiac cell-integrated microneedle patch for treating myocardial infarction.
(Science advances, 2018-11) Tang, Junnan; Wang, Jinqiang; Huang, Ke; Ye, Yanqi; Su, Teng; Qiao, Li; Hensley, Michael Taylor; Caranasos, Thomas George; Zhang, Jinying; Gu, Zhen; Cheng, Ke
We engineered a microneedle patch integrated with cardiac stromal cells (MN-CSCs) for therapeutic heart regeneration after acute myocardial infarction (MI). To perform cell-based heart regeneration, cells are currently delivered to the heart via direct muscle injection, intravascular infusion, or transplantation of epicardial patches. The first two approaches suffer from poor cell retention, while epicardial patches integrate slowly with host myocardium. Here, we used polymeric MNs to create "channels" between host myocardium and therapeutic CSCs. These channels allow regenerative factors secreted by CSCs to be released into the injured myocardium to promote heart repair. In the rat MI model study, the application of the MN-CSC patch effectively augmented cardiac functions and enhanced angiomyogenesis. In the porcine MI model study, MN-CSC patch application was nontoxic and resulted in cardiac function protection. The MN system represents an innovative approach delivering therapeutic cells for heart regeneration.
Open Access
Cardiac Stem Cell Patch Integrated with Microengineered Blood Vessels Promotes Cardiomyocyte Proliferation and Neovascularization after Acute Myocardial Infarction.
(ACS applied materials & interfaces, 2018-10) Su, Teng; Huang, Ke; Daniele, Michael A; Hensley, Michael Taylor; Young, Ashlyn T; Tang, Junnan; Allen, Tyler A; Vandergriff, Adam C; Erb, Patrick D; Ligler, Frances S; Cheng, Ke
Cardiac stem cell (CSC) therapy has shown preclinical and clinical evidence for ischemic heart repair but is limited by low cellular engraftment and survival after transplantation. Previous versions of the cardiac patch strategy improve stem cell engraftment and encourage repair of cardiac tissue. However, cardiac patches that can enhance cardiomyogenesis and angiogenesis at the injured site remain elusive. Therapies that target cardiomyocyte proliferation and new blood vessel formation hold great potential for the protection against acute myocardial infarction (MI). Here, we report a new strategy for creating a vascularized cardiac patch in a facile and modular fashion by leveraging microfluidic hydrodynamic focusing to construct the biomimetic microvessels (BMVs) that include human umbilical vein endothelial cells (HUVECs) lining the luminal surface and then encapsulating the BMVs in a fibrin gel spiked with human CSCs. We show that the endothelialized BMVs mimicked the natural architecture and function of capillaries and that the resultant vascularized cardiac patch (BMV-CSC patch) exhibited equivalent release of paracrine factors compared to those of coculture of genuine human CSCs and HUVECs after 7 days of in vitro culture. In a rat model of acute MI, the BMV-CSC patch therapy induced profound mitotic activities of cardiomyocytes in the peri-infarct region 4 weeks post-treatment. A significant increase in myocardial capillary density was noted in the infarcted hearts that received BMV-CSC patch treatment compared to the infarcted hearts treated with conventional CSC patches. The striking therapeutic benefits and the fast and facile fabrication of the BMV-CSC patch make it promising for practical applications. Our findings suggest that the BMV-CSC patch strategy may open up new possibilities for the treatment of ischemic heart injury.
Open Access
Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential.
(Journal of cell science, 2019-09) Allen, Tyler A; Asad, Dana; Amu, Emmanuel; Hensley, M Taylor; Cores, Jhon; Vandergriff, Adam; Tang, Junnan; Dinh, Phuong-Uyen; Shen, Deliang; Qiao, Li; Su, Teng; Hu, Shiqi; Liang, Hongxia; Shive, Heather; Harrell, Erin; Campbell, Connor; Peng, Xinxia; Yoder, Jeffrey A; Cheng, Ke
Metastasis accounts for the majority of all cancer deaths, yet the process remains poorly understood. A pivotal step in the metastasis process is the exiting of tumor cells from the circulation, a process known as extravasation. However, it is unclear how tumor cells extravasate and whether multicellular clusters of tumor cells possess the ability to exit as a whole or must first disassociate. In this study, we use in vivo zebrafish and mouse models to elucidate the mechanism tumor cells use to extravasate. We found that circulating tumor cells exit the circulation using the recently identified extravasation mechanism, angiopellosis, and do so as both clusters and individual cells. We further show that when melanoma and cervical cancer cells utilize this extravasation method to exit as clusters, they exhibit an increased ability to form tumors at distant sites through the expression of unique genetic profiles. Collectively, we present a new model for tumor cell extravasation of both individual and multicellular circulating tumor cells.This article has an associated First Person interview with the first author of the paper.
Open Access
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.
Open Access
Targeted repair of heart injury by stem cells fused with platelet nanovesicles.
(Nature biomedical engineering, 2018-01) Tang, Junnan; Su, Teng; Huang, Ke; Dinh, Phuong-Uyen; Wang, Zegen; Vandergriff, Adam; Hensley, Michael T; Cores, Jhon; Allen, Tyler; Li, Taosheng; Sproul, Erin; Mihalko, Emily; Lobo, Leonard J; Ruterbories, Laura; Lynch, Alex; Brown, Ashley; Caranasos, Thomas G; Shen, Deliang; Stouffer, George A; Gu, Zhen; Zhang, Jinying; Cheng, Ke
Stem cell transplantation, as used clinically, suffers from low retention and engraftment of the transplanted cells. Inspired by the ability of platelets to recruit stem cells to sites of injury on blood vessels, we hypothesized that platelets might enhance the vascular delivery of cardiac stem cells (CSCs) to sites of myocardial infarction injury. Here, we show that CSCs with platelet nanovesicles fused onto their surface membranes express platelet surface markers that are associated with platelet adhesion to injury sites. We also find that the modified CSCs selectively bind collagen-coated surfaces and endothelium-denuded rat aortas, and that in rat and porcine models of acute myocardial infarction the modified CSCs increase retention in the heart and reduce infarct size. Platelet-nanovesicle-fused CSCs thus possess the natural targeting and repairing ability of their parental cell types. This stem cell manipulation approach is fast, straightforward and safe, does not require genetic alteration of the cells, and should be generalizable to multiple cell types.