Browsing by Author "Guo, Rui"
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Item Open Access C1q/Tumor Necrosis Factor-Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways.(Circulation, 2017-11) Yan, Wenjun; Guo, Yongzhen; Tao, Ling; Lau, Wayne Bond; Gan, Lu; Yan, Zheyi; Guo, Rui; Gao, Erhe; Wong, G William; Koch, Walter L; Wang, Yajing; Ma, Xin-LiangBackground
Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair after myocardial infarction. CTRP9 (C1q/tumor necrosis factor-related protein-9) is a novel prosurvival cardiokine with significantly downregulated expression after myocardial infarction. Here we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting implanted stem cell survival and cardioprotection.Methods
Mice were subjected to myocardial infarction and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Survival, cardiac remodeling and function, cardiomyocytes apoptosis, and ADSCs engraftment were evaluated. Whether CTRP9 directly regulates ADSCs function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were used to uncover the molecular mechanisms of CTRP9.Results
Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 or P<0.01 versus CTRP9 alone), suggesting a synergistic effect. Administration of CTRP9 at a dose recovering physiological CTRP9 levels significantly prolonged ADSCs retention/survival after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9 knockout heart. In vitro study demonstrated that CTRP9 promoted ADSCs proliferation and migration, and it protected ADSCs against hydrogen peroxide-induced cellular death. CTRP9 enhances ADSCs proliferation/migration by extracellular regulated protein kinases (ERK)1/2-matrix metallopeptidase 9 signaling and promotes antiapoptotic/cell survival via ERK-nuclear factor erythroid-derived 2-like 2/antioxidative protein expression. N-cadherin was identified as a novel CTRP9 receptor mediating ADSCs signaling. Blockade of either N-cadherin or ERK1/2 completely abolished the previously noted CTRP9 effects. Although CTRP9 failed to promote ADSCs cardiogenic differentiation, CTRP9 promotes superoxide dismutase 3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death.Conclusions
We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms. These include binding with N-cadherin, activation of ERK-matrix metallopeptidase 9 and ERK-nuclear factor erythroid-derived 2-like 2 signaling, and upregulation/secretion of antioxidative proteins. These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy.Item Open Access Formation of Silica Microstructures between Inundated Stressed Silica Grains: Effect on Intergranular Tensile Strength(2014) Guo, RuiLaboratory tests on microscale are reported in which amorphous silica grains were compressed in a liquid environment, namely in solutions with different silica ion concentrations for up to four weeks. Such an arrangement represents an idealized representation of two sand grains. The grain surfaces and asperities were examined in Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) for fractures, silica polymer growth, and polymer strength. Single chains of silica polymers are found to have a failure pulling force of 330 - 450 nN.
A chain of observations are reported for the first time, using Pneumatic Grain Indenter and Grain Indenter-Puller apparatuses, confirming a long-existing hypothesis that a stressed contact with microcracks generates dissolved silica in the contact (asperity) vicinity, which eventually polymerizes, forming a structure between the grains on a timescale in the order of weeks. Such structure exhibits intergranular tensile force of 1 - 1.5 mN when aged in solutions containing silica ion concentrations of 200- to 500 ppm. Stress appears to accelerate the generation of silica polymers around stressed contact regions, so does mica-silica contacts. The magnitude of intergranular tensile force is 2 to 3 times greater than that of water capillary effect between grains.
Item Open Access Growth of gel microstructures between stressed silica grains and its effect on soil stiffening(2013) Guo, RuiLaboratory tests on microscale are reported in which two amorphous silica cubes were compressed in a liquid environment, namely in solutions with different silica ion concentrations for up to four weeks. Such an arrangement represents an idealized representation of two sand grains. The grain surfaces and asperities were examined in Scanning Electron Microscope (SEM) and Atomic Force Microscope (AFM) for fractures, silica gel growth, and polymer strength. In 500ppm solution, silica gel structures a few hundred microns long appeared between stressed silica cubes. In 200ppm solution, silica deposits were found around damaged grain surfaces, while at 90ppm (below silica solubility in neutral pH), fibers a few microns in length were found growing in cube cracks. AFM pulling tests found polymers with strength in the order of 100nN and length between 50 and 100 nm. After aging, size of silica gel is in the order of 10-100 µm with intergranular strength in the order of 0.01-1 mN. We concluded that prolonged compression produced damage in grains, raising local Si ion concentration, and accelerating precipitation, polymerization and gelation of silica on grain surfaces enhancing soil strength at the microscale, hence most likely contributing to the aging phenomenon observed at the macroscale. Mica surfaces near stressed silica contacts were also found to enhance silica gel growth.
Item Open Access Restoring diabetes-induced autophagic flux arrest in ischemic/reperfused heart by ADIPOR (adiponectin receptor) activation involves both AMPK-dependent and AMPK-independent signaling.(Autophagy, 2017-01) Wang, Yajing; Liang, Bin; Lau, Wayne Bond; Du, Yunhui; Guo, Rui; Yan, Zheyi; Gan, Lu; Yan, Wenjun; Zhao, Jianli; Gao, Erhe; Koch, Walter; Ma, Xin-LiangMacroautophagy/autophagy is increasingly recognized as an important regulator of myocardial ischemia-reperfusion (MI-R) injury. However, whether and how diabetes may alter autophagy in response to MI-R remains unknown. Deficiency of ADIPOQ, a cardioprotective molecule, markedly increases MI-R injury. However, the role of diabetic hypoadiponectinemia in cardiac autophagy alteration after MI-R is unclear. Utilizing normal control (NC), high-fat-diet-induced diabetes, and Adipoq knockout (adipoq-/-) mice, we demonstrated that autophagosome formation was modestly inhibited and autophagosome clearance was markedly impaired in the diabetic heart subjected to MI-R. adipoq-/- largely reproduced the phenotypic alterations observed in the ischemic-reperfused diabetic heart. Treatment of diabetic and adipoq-/- mice with AdipoRon, a novel ADIPOR (adiponectin receptor) agonist, stimulated autophagosome formation, markedly increased autophagosome clearance, reduced infarct size, and improved cardiac function (P < 0.01 vs vehicle). Mechanistically, AdipoRon caused significant phosphorylation of AMPK-BECN1 (Ser93/Thr119)-class III PtdIns3K (Ser164) and enhanced lysosome protein LAMP2 expression both in vivo and in isolated adult cardiomyocytes. Pharmacological AMPK inhibition or genetic Prkaa2 mutation abolished AdipoRon-induced BECN1 (Ser93/Thr119)-PtdIns3K (Ser164) phosphorylation and AdipoRon-stimulated autophagosome formation. However, AdipoRon-induced LAMP2 expression, AdipoRon-stimulated autophagosome clearance, and AdipoRon-suppressed superoxide generation were not affected by AMPK inhibition. Treatment with MnTMPyP (a superoxide scavenger) increased LAMP2 expression and stimulated autophagosome clearance in simulated ischemic-reperfused cardiomyocytes. However, no additive effect between AdipoRon and MnTMPyP was observed. Collectively, these results demonstrate that hypoadiponectinemia impairs autophagic flux, contributing to enhanced MI-R injury in the diabetic state. ADIPOR activation restores AMPK-mediated autophagosome formation and antioxidant-mediated autophagosome clearance, representing a novel intervention effective against MI-R injury in diabetic conditions.