77 results on '"Weisel, Richard D."'
Search Results
52. Uterine cells are recruited to the infarcted heart and improve cardiac outcomes in female rats
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Xaymardan, Munira, Sun, Zhuo, Hatta, Kota, Tsukashita, Masaki, Konecny, Filip, Weisel, Richard D., and Li, Ren-Ke
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HEART injuries , *ECHOCARDIOGRAPHY , *BLOOD vessels , *GREEN fluorescent protein , *VASCULAR endothelial growth factor receptors , *LABORATORY rats - Abstract
Abstract: We evaluated the hypothesis that uterine cells home to the heart after injury and improve cardiac outcomes. Premenopausal women have fewer cardiovascular complications than age-matched men, but the mechanisms responsible for this protection have not been conclusively identified. Hysterectomy was performed in young female rats (leaving the ovaries intact), and 7days later the left coronary artery was ligated to produce a myocardial infarction (MI). Cardiac function at 28days post-MI was measured using echocardiography. Fractional shortening was best in non-hysterectomized (non-Hx) females and lower in both Hx females and males. Uteri were then removed from GFP rats and heterotopically transplanted into non-GFP recipients to investigate homing of uterine cells to the infarcted myocardium. Seven days later, the uterine transplant recipients underwent coronary ligation. GFP+ cells were found in the recipient hearts 7days after MI and persisted for 6months. Confocal analysis showed that homed uterine cells were located around blood vessels, suggesting their involvement in neovascularization. We then evaluated uterine cell transplantation by intravenously injecting GFP+ uterine cells into Hx females immediately after MI. These GFP+ cells were found to home to the injured myocardium, stimulate angiogenesis, improve cardiac function, and increase survival. This study demonstrates that uterine cells can home to the injured myocardium, enhance tissue repair, and prevent cardiac dysfunction. Uterine cells may play a role in the prevention of cardiovascular complications in females. [Copyright &y& Elsevier]
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- 2012
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53. Biodegradable collagen patch with covalently immobilized VEGF for myocardial repair
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Miyagi, Yasuo, Chiu, Loraine L.Y., Cimini, Massimo, Weisel, Richard D., Radisic, Milica, and Li, Ren-Ke
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BIODEGRADATION , *COLLAGEN , *VASCULAR endothelial growth factors , *CARDIAC surgery , *MYOCARDIAL infarction , *TISSUE engineering , *RIGHT heart ventricle , *NEOVASCULARIZATION - Abstract
Abstract: Vascularization of engineered tissues in vitro and in vivo remains a key problem in translation of engineered tissues to clinical practice. Growth factor signalling can be prolonged by covalent tethering, thus we hypothesized that covalent immobilization of vascular endothelial growth factor (VEGF-165) to a porous collagen scaffold will enable rapid vascularization in vivo. Covalent immobilization may be preferred over controlled release or cell transfection if the effects are desired within the biomaterial rather than the surrounding tissue. Scaffolds were prepared with 14.5 ± 1.4 ng (Low) or 97.2 ± 8.0 ng (High) immobilized VEGF, or left untreated (control), and used to replace a full right ventricular free wall defect in rat hearts. In addition to rapid vascularization, an effective cardiac patch should exhibit neither thinning nor dilatation upon implantation. In vitro, VEGF enhanced the growth of endothelial and bone marrow cells seeded onto scaffolds. In vivo, High VEGF patches had greater blood vessel density (p < 0.01) than control at Day 7 and 28 due to increased cell recruitment and proliferation (p < 0.05 vs. control). At Day 28, VEGF-treated patches were significantly thicker (p < 0.05) than control, and thickness correlated positively with neovascularization (r = 0.67, p = 0.023). Importantly, angiogenesis in VEGF scaffolds contributed to improved cell survival and tissue formation. [ABSTRACT FROM AUTHOR]
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- 2011
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54. Infarct stabilization and cardiac repair with a VEGF-conjugated, injectable hydrogel
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Wu, Jun, Zeng, Faquan, Huang, Xi-Ping, Chung, Jennifer C.-Y., Konecny, Filip, Weisel, Richard D., and Li, Ren-Ke
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TISSUE scaffolds , *BIOMEDICAL materials , *MYOCARDIAL infarction , *VASCULAR endothelial growth factors , *ECHOCARDIOGRAPHY , *NEOVASCULARIZATION , *TISSUE engineering , *CYTOKINES , *COLLOIDS in medicine - Abstract
Abstract: Injectable scaffolds made of biodegradable biomaterials can stabilize a myocardial infarct and promote cardiac repair. Here, we describe the synthesis of a new, temperature-sensitive, aliphatic polyester hydrogel (HG) conjugated with vascular endothelial growth factor (VEGF) and evaluate its effects on cardiac recovery after a myocardial infarction (MI). Seven days after coronary ligation in rats, PBS, HG, or HG mixed or conjugated with VEGF (HG + VEGF or HG-VEGF, respectively) was injected around the infarct (n = 8–11/group). Function was evaluated by echocardiography at multiple time points. Pressure–volume measurements were taken and infarct morphometry and blood vessel density were assessed at 35 days after injection. HG-VEGF provided localized, sustained VEGF function. Compared with outcomes in the PBS group, fractional shortening, ventricular volumes, preload recruitable stroke work, and end-systolic elastance were all preserved (p < 0.05) in the HG and HG + VEGF groups, and further preserved in the HG-VEGF group. Conjugated VEGF also produced the highest blood vessel density (p < 0.05). The infarct thinned and dilated after PBS injection, but was smaller and thicker in hearts treated with HG (p < 0.05). Our temperature-sensitive HG attenuated adverse cardiac remodeling and improved ventricular function when injected after an MI. VEGF delivery enhanced these effects when the VEGF was conjugated to the HG. [ABSTRACT FROM AUTHOR]
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- 2011
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55. Surgical ventricular restoration with a cell- and cytokine-seeded biodegradable scaffold
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Miyagi, Yasuo, Zeng, Faquan, Huang, Xi-Ping, Foltz, Warren D., Wu, Jun, Mihic, Anton, Yau, Terrence M., Weisel, Richard D., and Li, Ren-Ke
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LEFT heart ventricle surgery , *CYTOKINES , *BIODEGRADATION , *TISSUE scaffolds , *LABORATORY rats , *BONE marrow cells , *TISSUE engineering , *ECHOCARDIOGRAPHY - Abstract
Abstract: Late after a myocardial infarction (MI), surgical ventricular restoration (SVR) can reduce left ventricular volumes, but an enhanced cardiac patch may be required to restore function. We developed a new, biodegradable patch (modified gelfoam, MGF) consisting of a spongy inner core (gelfoam) to encourage cell engraftment and an outer coating (poly ε-caprolactone) to provide sufficient strength to permit ventricular repair. Two weeks after coronary ligation in rats, SVR was performed using one of the following: gelfoam, MGF, MGF patches with hydrogel alone, or with hydrogel and cytokines (stem cell factor, stromal cell-derived factor-1α), bone marrow mesenchymal stem cells, or both. Cardiac function and morphology were evaluated by echocardiography, conduction catheterization, magnetic resonance imaging, and histology. Animals whose hearts were repaired with untreated gelfoam died of ventricular rupture. The MGF groups had significantly improved myocardial systolic function vs. MI controls. Enhancement with cytokines and/or cells promoted more α-smooth muscle actin-positive cells, more capillaries, greater wall thickness, a more ellipsoid shape, greater fractional shortening, and better-preserved systolic elastance than MGF alone. This combination of the new, reinforced, biodegradable biomaterial and cytokine/cell treatment created a viable tissue after SVR and produced better functional outcomes than un-reinforced gelfoam or MGF alone. [ABSTRACT FROM AUTHOR]
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- 2010
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56. What's New in Cardiac Cell Therapy? Allogeneic Bone Marrow Stromal Cells as “Universal Donor Cells”.
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Kinkaid, Heather Y. McDonald, Huang, Xi-Ping, Li, Ren-Ke, and Weisel, Richard D.
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CELLULAR therapy , *HEART cells , *HEART failure treatment , *BONE marrow , *STEM cells , *CLINICAL trials , *IMMUNITY - Abstract
Cardiac cell therapies offer distinct and exciting advantages over current treatments to prevent postinfarction heart failure because they can reverse ventricular remodeling and improve function, but only if the implanted stem cells contribute biological functions and achieve prolonged engraftment within the hostile environment of the damaged heart. Unfortunately, function is diminished in autologous stem cells isolated from older patients and those with comorbidities, and so clinical trials testing the implantation of healthy, allogeneic bone marrow–derived stromal cells (MSCs) isolated from young donors are currently underway. MSCs are unique because, in addition to exerting paracrine effects that restore blood flow and recruit endogenous stem cells to the infarct, they exhibit immune-modulating properties in culture that—if retained after allogeneic implantation—imply the cells may escape immune recognition within the heart. At present, the scope of MSC immune modulation after implantation is unclear. (J Card Surg 2010;25:359-366) [ABSTRACT FROM AUTHOR]
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- 2010
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57. On “Acute Effect of Cerivastatin on Cardiac Regional Ischemia in a Rat Model Mimicking Off-pump Coronary Surgery”.
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Borger, Michael A., Fazel, Shafie, and Weisel, Richard D.
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CORONARY disease , *CARDIAC surgery , *INFARCTION , *ISCHEMIA , *LABORATORY rats - Abstract
Studies the potential beneficial effects of cerivastatin on temporary regional myocardial ischemia. Determination of whether cerivastatin has an effect on the area at risk and infarction after reperfusion; Employment of a temporary coronary artery occlusion model in rats; Ability of cerivastatin to increase myocardial tolerance to prolonged temporary ischemia.
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- 2005
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58. Improvement in cardiac function after bone marrow cell thearpy is associated with an increase in myocardial inflammation.
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Jie Sun, Shu-Hong Li, Shi-Ming Liu, Jun Wu, Weisel, Richard D., Yu-Feng Zhuo, Yau, Terrence M., Ren-Ke Li, and Fazel, Shafie S.
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BONE marrow cells , *CELL transplantation , *MYOCARDIAL infarction , *INFLAMMATION , *HEMODYNAMICS , *MYOFIBROBLASTS - Abstract
The mechanisms for the beneficial impact of bone marrow cell (BMC) therapy after myocardial infarction (MI) are ill defined. We hypothesized that the implanted cells improve function by attenuating post-MI inflammation and repair. In mice, 3 X 10[sup5] fresh BMCs were implanted immediately after coronary ligation. Cardiac function was evaluated over time. Inflammatory cytokines and cells were measured, and their impacts on the (myo)fibroblastic repair response, angiogenesis, and scar formation were determined. All differences below had P values of <0.05. BMC implantation reduced the decline in fractional shortening and ventricular dilation. Invasive hemodynamics confirmed a difference in systolic function at day 7 and diastolic function at day 28 favoring the BMC group. Interestingly, BMC implantation caused a 1.6-fold in- crease in the number of macrophages infiltrating the infarct but did not affect neutrophils. This increase was associated with a 1.9-fold higher myocardial TNF-α level. The heightened inflammatory response was associated with a 1.4-fold induction of transforming growth factor-β and a 1.3-fold induction of basic fibroblast growth factor. These changes resulted in a 1.6-fold increase in α-smooth muscle actin and a 1 .9-fold increase in total discoidin domain receptor 2-expressing cells in the BMC group. These two markers are expressed by cardiac (myo)fibroblasts. Capillary density in the border zone increased 2.0- fold. Consistent with a more robust repair-mediated scar "contracture," the final scar size was 0.7-fold smaller in the BMC group. In conclusion, after MI, BMC therapy induced a more robust inflammatory response that improved the "priming" of the (myo)fibroblast repair phase. Enhancing this response may further improve the beneficial impact of cellular therapy. [ABSTRACT FROM AUTHOR]
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- 2009
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59. Activation of c-kit is necessary for mobilization of reparative bone marrow progenitor cells in response to cardiac injury.
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Fazel, Shafie S., Liwen Chen, Angoulvant, Denis, Shu-Hong Li, Weisel, Richard D., Keating, Armand, and Ren-Ke Li
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CARDIOVASCULAR diseases , *BONE marrow , *PROTEIN-tyrosine kinases , *CELL motility , *METALLOPROTEINASES , *ISCHEMIA , *HEART failure , *MYOCARDIAL infarction - Abstract
Cardiovascular disease is the numberone cause of mortality in the developed world. The aim of this study is to define the mechanisms by which bone marrow progenitor cells are mobilized in response to cardiac ischemic injury. We used a closed-chest model of murine cardiac infarction/reperfusion, which segregated the surgical thoracotomy from the induction of cardiac infarction, so that we could study isolated fluctuations in cytokines without the confounding impact of surgery. We show here that bone marrow activation of the c-kit tyrosine kinase receptor in response to released soluble KitL is necessary for bone marrow progenitor cell mobilization after ischemic cardiac injury. We also show that release of KitL and c-kit activation require the activity of matrix metallo-proteinase-9 within the bone marrow compartment. Finally, we demonstrate that mice with c-kit dysfunction develop cardiac failure after myocardial infarction and that bone marrow transplantation rescues the failing cardiac phenotype. In light of the ongoing trials of progenitor cell therapy for heart disease, our study outlines the endogenous repair mechanisms that are invoked after cardiac injury. Amplification of this pathway may aid in restoration of cardiac function after myocardial infarction. [ABSTRACT FROM AUTHOR]
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- 2008
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60. The MRL mouse heart does not recover ventricular function after a myocardial infarction
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Cimini, Massimo, Fazel, Shafie, Fujii, Hiroko, Zhou, Sun, Tang, Gilbert, Weisel, Richard D., and Li, Ren-Ke
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LABORATORY mice , *HEART blood-vessels , *MYOCARDIAL infarction , *CARDIAC imaging - Abstract
Abstract: Introduction: Murphy Roth Large (MRL) mice have a remarkable regenerative capacity. A recent report demonstrated rapid cardiac healing in these mice following cryogenically induced right ventricular injury, suggesting the potential for new regenerative therapies to restore cardiac function in mammals. We therefore evaluated the cardiac regenerative wound-healing response and functional recovery of MRL mice in response to a clinically relevant left ventricular coronary ligation. Methods: Female MRL/MpJ+/+ and C57BL/6 mice underwent left coronary artery ligation. Cardiac function was evaluated by echocardiography at Days 0, 5, 15, and 60. At Day 96, invasive hemodynamics were assessed by pressure–volume loops using a Millar catheter. Hearts were perfusion fixed for histomorphometric analysis at Days 5, 15, and 96. Some hearts were fresh frozen at Days 5 and 15 for immunohistochemical analysis and digital quantitation of blood vessel density (CD31) and cellular proliferation (Ki67). Results: MRL mice healed ear punch wounds (89% reduction in area) more extensively than C57BL/6 mice (28% reduction in area) but did not differ functionally from C57BL/6 animals before or after coronary ligation. In addition, blood vessel density and cell proliferation were similar between the two strains. Conclusions: Although MRL mice rapidly healed ear injury, they did not exhibit regeneration of the left ventricle or enhanced functional improvement in response to coronary ligation. The prospect of cardiac regeneration after myocardial infarction will require further studies designed to elucidate the possible mechanisms of functional restoration. [Copyright &y& Elsevier]
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- 2008
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61. TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction
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Tian, Hai, Cimini, Massimo, Fedak, Paul W.M., Altamentova, Svetlana, Fazel, Shafie, Huang, Ming-Li, Weisel, Richard D., and Li, Ren-Ke
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HEART diseases , *CARDIAC imaging , *RODENTS , *BLOOD circulation disorders - Abstract
Abstract: The activity of TIMP-3, a natural tissue inhibitor of matrix metalloproteinases (MMPs), is decreased in the failing heart. This study evaluated the response to coronary ligation of cardiac structure, function, and matrix remodeling in wild-type (WT) mice, and those deficient in TIMP-3 (timp-3 −/− ). The coronary artery was ligated in timp-3 −/− and age-matched WT mice. At various time points over the following 28-day period, left ventricular structure and function (by echocardiography, pressure–volume measurements and morphometry), MMP levels and activity, blood vessel density, cell proliferation, apoptosis, matrix structure, and inflammatory cytokine levels were assessed in both groups. After ligation, mortality was significantly greater in timp-3 −/− than in WT mice. Morphometry and echocardiography demonstrated no difference in heart size or function prior to ligation; however, the progression of left ventricular systolic dysfunction was accelerated in timp-3 −/− mice at 7, 14 and 28 days after infarction compared to WT controls. Left ventricular dilatation, gelatinase MMP activity, and TNF-α levels were significantly greater in timp-3 −/− than in WT mice at different times after ligation. By histological evaluation, timp-3 −/− mice exhibited significantly increased blood vessel density, cell proliferation, and apoptosis in the infarct area, and reduced collagen content in the viable remote myocardium compared to WT mice at 7 and 14 days after ligation. TIMP-3 deficiency accelerated maladaptive cardiac remodeling after a myocardial infarction by promoting matrix degradation and inflammatory cytokine expression. This study supports further investigations to determine whether such remodeling could be reduced by augmenting TIMP-3 expression in the infarcted myocardium. [Copyright &y& Elsevier]
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- 2007
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62. Combined transmyocardial revascularization and cell-based angiogenic gene therapy increases transplanted cell survival.
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Spiegeistein, Dan, Kim, Christopher, Yaoguang Zhang, Guangming Li, Weisel, Richard D., Ren-Ke Li,, and Yau, Terrence M.
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RESEARCH , *HUMAN physiology , *MYOCARDIAL revascularization , *HYPOGLYCEMIC agents , *THERAPEUTICS - Abstract
We hypothesized that pretreatment of an infarcted heart by mechanical transmyocardial revascularization (TMR) before transplantation of bone marrow cells (BMCs) or BMC-expressing angiogenic growth factors would increase transplanted BMC survival and enhance myocardial repair. Female Lewis rats underwent coronary ligation 3 wk before creation of 10 needle TMR channels (3 groups) or no TMR (3 groups), followed by transplantation of 3 × 106 male donor BMCs, BMC transfected with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1) (BMC + VBI), or medium alone. At 1, 3, and 7 days, we evaluated transplanted cell survival, vascular densities, and left ventricular (LV) function (N = 4 per group × 6 groups × 3 time points). At 3 days, vascular densities in the scar were increased by TMR + BMC + VBI and by BMC + VBI (P < 0.05), and at 7 days, vascular densities were greatest in rats receiving TMR + BMC + VBI (P < 0.05). Transplanted cell survival at 3 and 7 days was increased by TMR and by BMC + VBI. Combined therapy with TMR + BMC + VBI resulted in the greatest cell survival at 3 days (P < 0.05) versus BMC. After 7 days, LV ejection fraction (LVEF) was lowest in rats receiving neither BMC nor TMR and greatest in rats receiving TMR + BMC + VBI (P = 0.004). We concluded that mechanical pretreatment of infarcted myocardium by TMR enhances the effect of subsequent cell-based gene therapy on transplanted cell survival, angiogenesis, and LV function. Scar pretreatment with TMR combined with cell-based multigene therapy may maximize myocardial repair. [ABSTRACT FROM AUTHOR]
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- 2007
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63. Myometrial cells induce angiogenesis and salvage damaged myocardium.
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Ming-Li Huang, Hai Tian, Jun Wu, Matsubayashi, Keiji, Weisel, Richard D., and Ren-Ke Li
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MYOMETRIUM , *CELLS , *LABORATORY rats , *MYOCARDIUM , *HEART - Abstract
Characteristically, uterine myometrial cells (MCs) are proliferative, inducing angio- genesis within the female reproductive organ. We evaluated whether MCs implanted into myocardium could also induce angiogenesis and restore heart function after injury. MCs were isolated from the adult rat uterus and cultured for three studies: 1) Intracellular VEGF levels were measured in MCs cultured with progesterone (10-11, 10-9, and 10-7 M) (n = 6 tests per group). 2) Blood vessel density was evaluated 8 days after MCs (3 × 106 or 6 × 106), smooth muscle cells (SMCs), or endothelial cells (n = 6 rats per group) were injected with matrigel into the subcutaneous tissue of adult rats. 3) MCs, SMCs (5 × 106/rat), or media were injected into a transmural scar 3 wk after cryoinjury in rat hearts (n = 12 rats per group), and heart function, blood vessel density, and myocardial scar size and thickness were evaluated 5 wk later. In study 1, cultured MCs expressed VEGF, with levels significantly (P < 0.05) upregulated by progesterone at an optimal dose of 10-11 M. In study 2, MCs injected into the subcutaneous tissue with matrigel induced significantly more blood vessels, especially large-diameter vessels, than did SMCs or endothelial cells (P < 0.01 for all groups). This angiogenic effect was greatest (P < 0.01) at higher doses of MCs and was enhanced by progesterone (10-11 M). In study 3, MCs implanted into the injured myocardium increased blood vessel density at the implant area, reduced scar size, and improved cardiac function relative to SMCs and media. Overall, MCs induced angiogenesis in vitro and in vivo, prevented cardiac remodeling, and improved heart functional recovery after cardiac injury. [ABSTRACT FROM AUTHOR]
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- 2006
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64. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines.
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Fazel, Shafie, Cimini, Massimo, Liwen Chen, Shuhong Li, Angoulvant, Denis, Fedak, Paul, Verma, Subodh, Weisel, Richard D., Keating, Armand, and Ren-Ke Li
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BONE marrow , *VASCULAR endothelial growth factors , *CYTOKINES , *CELLULAR therapy , *MYOFIBROBLASTS , *CARCINOGENESIS , *PHENOTYPES - Abstract
Clinical trials of bone marrow stem/progenitor cell therapy after myocardial infarction (MI) have shown promising results, but the mechanism of benefit is unclear. We examined the nature of endogenous myocardial repair that is dependent on the function of the c-kit receptor, which is expressed on bone marrow stem/progenitor cells and on recently identified cardiac stem cells. MI increased the number of c-kit+ cells in the heart. These cells were traced back to a bone marrow origin, using genetic tagging in bone marrow chimeric mice. The recruited c-kit+ cells established a proangiogenic milieu in the infarct border zone by increasing VEGF and by reversing the cardiac ratio of angiopoietin-1 to angiopoietin-2. These oscillations potentiated endothelial mitogenesis and were associated with the establishment of an extensive myofibroblast rich repair tissue. Mutations in the c-kit receptor interfered with the mobilization of the cells to the heart, prevented angiogenesis, diminished myofibroblast-rich repair tissue formation, and led to precipitous cardiac failure and death. Replacement of the mutant bone marrow with wild-type cells rescued the cardiomyopathic phenotype. We conclude that, consistent with their documented role in tumorigenesis, bone marrow c-kit+ cells act as key regulators of the angiogenic switch in infarcted myocardium, thereby driving efficient cardiac repair. [ABSTRACT FROM AUTHOR]
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- 2006
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65. Increasing donor age adversely impacts beneficial effects of bone marrow but not smooth muscle myocardial cell therapy.
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Hao Zhang, Fazel, Shafie, Hai Tian, Mickle, Donald A. G., Weisel, Richard D., Fujii, Takeshiro, and Ren-Ke Li
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BONE marrow , *SMOOTH muscle , *CELLULAR therapy , *ORGAN donors , *CARDIOMYOPATHIES - Abstract
We evaluated the impact of donor age on the efficacy of myocardial cellular therapy for ischemic cardiomyopathy. Characteristics of smooth muscle cells (SMC), bone marrow stromal cells (MSCs), and skeletal muscle cells (SKMCs) from young, adult, and old rats were compared in vitro. Three weeks after coronary ligation, 3.5 million SMCs (n = 11) or MSCs (n = 9) from old syngenic rats or culture medium (n = 6) were injected into the ischemic region. Five weeks after implantation, cardiac function was assessed by echocardiography and the Langendorff apparatus. In the in vitro study, the numbers and proliferation of MSCs from fresh bone marrow and SKMCs from fresh tissue but not SMCs were markedly diminished in old animals (P < 0.05 both groups). SKMCs from old animals did not reach confluence. After treatment with 5-azacytidine (azacitidine), the myogenic potential of old MSCs was decreased compared with young MSCs. In the in vivo study, both SMC and MSC transplantation induced significant angiogenesis compared with media injections (P < 0.05 both groups). Transplantation of SMCs but not MSCs prevented scar thinning (P = 0.03) and improved ejection fraction and fractional shortening (P < 0.05). Load-independent indices of cardiac function in a Langendorff preparation confirmed improved function in the aged SMC group (P = 0.01) but not in the MSC group compared with the control group. In conclusion, donor age adversely impacts the efficacy of cellular therapy for myocardial regeneration and is cell-type dependent. SMCs from old donors retain their ability to improve cardiac function after implantation into ischemic myocardium. [ABSTRACT FROM AUTHOR]
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- 2005
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66. Stem cells in clinical practice
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Evers, B Mark, Weissman, Irving L, Flake, Alan W, Tabar, Viviane, and Weisel, Richard D
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- 2003
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67. Cell transplantation to improve ventricular function in the failing heart
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Tang, Gilbert H.L., Fedak, Paul W.M., Yau, Terrence M., Weisel, Richard D., Kulik, Alex, Mickle, Donald A.G., and Li, Ren-Ke
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HEART failure , *CELL transplantation - Abstract
Current therapies for congestive heart failure are limited in efficacy or in applicability. Cardiac cell transplantation offers a novel therapeutic approach to improve heart function. Although significant progress has been made over the past decade in the development of cell transplantation, only recently have investigators studied the changes in ventricular function following cell transplantation. This review article describes the latest research developments, evaluates recent studies of ventricular function after cell transplantation, and discusses the future directions of cell transplantation as a new therapy to ‘repair broken hearts’. [Copyright &y& Elsevier]
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- 2003
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68. The conductive function of biopolymer corrects myocardial scar conduction blockage and resynchronizes contraction to prevent heart failure.
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He, Sheng, Wu, Jun, Li, Shu-Hong, Wang, Li, Sun, Yu, Xie, Jun, Ramnath, Daniel, Weisel, Richard D., Yau, Terrence M., Sung, Hsing-Wen, and Li, Ren-Ke
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CARDIAC contraction , *HEART failure , *SCARS , *ARRHYTHMIA , *MYOCARDIAL infarction - Abstract
Myocardial fibrosis, resulting from ischemic injury, increases tissue resistivity in the infarct area, which impedes heart synchronous electrical propagation. The uneven conduction between myocardium and fibrotic tissue leads to dys-synchronous contraction, which progresses towards ventricular dysfunction. We synthesized a conductive poly-pyrrole-chitosan hydrogel (PPY–CHI), and investigated its capabilities in improving electrical propagation in fibrotic tissue, as well as resynchronizing cardiac contraction to preserve cardiac function. In an in vitro fibrotic scar model, conductivity increased in proportion to the amount of PPY-CHI hydrogel added. To elucidate the mechanism of interaction between myocardial ionic changes and electrical current, an equivalent circuit model was used, which showed that PPY-CHI resistance was 10 times lower, and latency time 5 times shorter, compared to controls. Using a rat myocardial infarction (MI) model, PPY-CHI was injected into fibrotic tissue 7 days post MI. There, PPY-CHI reduced tissue resistance by 30%, improved electrical conduction across the fibrotic scar by 33%, enhanced field potential amplitudes by 2 times, and resynchronized cardiac contraction. PPY-CHI hydrogel also preserved cardiac function at 3 months, and reduced susceptibility to arrhythmia by 30% post-MI. These data demonstrated that the conductive PPY-CHI hydrogel reduced fibrotic scar resistivity, and enhanced electrical conduction, to synchronize cardiac contraction. [ABSTRACT FROM AUTHOR]
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- 2020
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69. A self-doping conductive polymer hydrogel that can restore electrical impulse propagation at myocardial infarct to prevent cardiac arrhythmia and preserve ventricular function.
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Zhang, Chongyu, Hsieh, Meng-Hsuan, Wu, Song-Yi, Li, Shu-Hong, Wu, Jun, Liu, Shi-Ming, Wei, Hao-Ji, Weisel, Richard D., Sung, Hsing-Wen, and Li, Ren-Ke
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ARRHYTHMIA , *CONDUCTING polymers , *MYOCARDIAL infarction , *VENTRICULAR arrhythmia , *CARDIAC contraction , *POLYMERSOMES - Abstract
Following myocardial infarction (MI), necrotic cardiomyocytes (CMs) are replaced by fibroblasts and collagen tissue, causing abnormal electrical signal propagation, desynchronizing cardiac contraction, resulting in cardiac arrhythmia. In this work, a conductive polymer, poly-3-amino-4-methoxybenzoic acid (PAMB), is synthesized and grafted onto non-conductive gelatin. The as-synthesized PAMB-G copolymer is self-doped in physiological pH environments, making it an electrically active material in biological tissues. This copolymer is cross-linked by carbodiimide to form an injectable conductive hydrogel (PAMB-G hydrogel). The un-grafted gelatin hydrogel is prepared in a similar manner as a control. Both test hydrogels not only provide an optimal matrix for CM adhesion and growth but also maintain CM morphology and functional proteins. The conductivity of PAMB-G hydrogel is ca. 12 times higher than that of gelatin hydrogel. Microelectrode array analyses reveal that a heart placed on the PAMB-G hydrogel has a higher field potential amplitude than that placed on the gelatin hydrogel and can pass current from one heart to excite another heart at a distance. The injection of PAMB-G hydrogel into the scar zone following an MI in a rat heart improves electrical impulse propagation over that in a heart that has been treated with gelatin hydrogel, and synchronizes heart contraction, leading to preservation of the ventricular function and reduction of cardiac arrhythmia, demonstrating its potential for use in treating MI. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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70. Long‐term repopulation of aged bone marrow stem cells using young Sca‐1 cells promotes aged heart rejuvenation.
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Li, Jiao, Li, Shu‐Hong, Dong, Jun, Alibhai, Faisal J., Zhang, Chongyu, Shao, Zheng‐Bo, Song, Hui‐Fang, He, Sheng, Yin, Wen‐Juan, Wu, Jun, Weisel, Richard D., Liu, Shi‐Ming, and Li, Ren‐Ke
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BONE marrow cells , *STEM cells , *DNA microarrays , *CARDIAC regeneration , *PROTEIN microarrays - Abstract
Reduced quantity and quality of stem cells in aged individuals hinders cardiac repair and regeneration after injury. We used young bone marrow (BM) stem cell antigen 1 (Sca‐1) cells to reconstitute aged BM and rejuvenate the aged heart, and examined the underlying molecular mechanisms. BM Sca‐1+ or Sca‐1− cells from young (2–3 months) or aged (18–19 months) GFP transgenic mice were transplanted into lethally irradiated aged mice to generate 4 groups of chimeras: young Sca‐1+, young Sca‐1−, old Sca‐1+, and old Sca‐1−. Four months later, expression of rejuvenation‐related genes (Bmi1, Cbx8, PNUTS, Sirt1, Sirt2, Sirt6) and proteins (CDK2, CDK4) was increased along with telomerase activity and telomerase‐related protein (DNA‐PKcs, TRF‐2) expression, whereas expression of senescence‐related genes (p16INK4a, P19ARF, p27Kip1) and proteins (p16INK4a, p27Kip1) was decreased in Sca‐1+ chimeric hearts, especially in the young group. Host cardiac endothelial cells (GFP−CD31+) but not cardiomyocytes were the primary cell type rejuvenated by young Sca‐1+ cells as shown by improved proliferation, migration, and tubular formation abilities. C‐X‐C chemokine CXCL12 was the factor most highly expressed in homed donor BM (GFP+) cells isolated from young Sca‐1+ chimeric hearts. Protein expression of Cxcr4, phospho‐Akt, and phospho‐FoxO3a in endothelial cells derived from the aged chimeric heart was increased, especially in the young Sca‐1+ group. Reconstitution of aged BM with young Sca‐1+ cells resulted in effective homing of functional stem cells in the aged heart. These young, regenerative stem cells promoted aged heart rejuvenation through activation of the Cxcl12/Cxcr4 pathway of cardiac endothelial cells. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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71. A novel technique to assess flow-mediated vasodilation.
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Fazel S, Weisel RD, Verma S, Fazel, Shafie, Weisel, Richard D, and Verma, Subodh
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- 2004
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72. Abstract 12278: High Autophagy Rate in Young Sca-1+ Bone Marrow Cells Promotes a Pro-Rejuvenating Phenotype in the Heart via Improving Autophagy.
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Yeganeh, Azadeh, Alibhai, Faisal J, Tobin, Stephanie W, Wu, Jun, Weisel, Richard D, and Li, Ren-Ke
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BONE marrow cells , *HEART cells , *CELL migration , *STEM cells , *BONE marrow - Abstract
Introduction: Cardiovascular disease is the leading cause of death worldwide and its prevalence increases with age. Replacing the bone marrow (BM) stem cells of aged mice with young BM stem cell antigen-1+ (Y-Sca-1+) cells rejuvenates the response of the aged heart to injury. Autophagy, a critical cellular recycling process, decreases with age. We hypothesized that the high rate of autophagy in Y-Sca-1+ BM cells contributes to the rejuvenation of the aged heart and improves tissue repair. Methods: In vitro: Young (Y) and old (O) Sca-1+ BM cells were isolated from Y and O mice and cultured in normoxia and hypoxia conditions to examine the rate of autophagy. To determine the effect of secretory factors, conditioned medium (CM) was produced from Y-Sca-1+ and O-Sca-1+ cells and used to culture old primary cardiac fibroblasts (O-Fs). In vivo: Old mice were lethally irradiated and reconstituted with Y-Sca-1+ or O-Sca-1+ BM cells from GFP mice to generate YP and OP chimeras, respectively. After 3 months, mice were sacrificed and hearts collected for molecular and histological analyses. Results: In vitro: Cultured Y-Sca-1+ cells exhibited a higher rate of autophagy and were more responsive to hypoxia-induced autophagy than O-Sca-1+ cells. Thus, Y-Sca-1+ cells may pre-condition and rejuvenate the aged heat. In support of this theory, factors secreted from Y-Sca-1+, but not O-Sca-1+ BM cells, enhanced several functions of O-Fs, including autophagy, cell migration, proliferation and trans-differentiation. This phenotype was not observed after boiling the CM, suggesting that rejuvenation is mediated by a secreted factor. In vivo: We found that reconstitution of aged mice with Y-Sca-1+ BM cells improved autophagy of the aged heart. The autophagy rate was increased in YP relative to OP hearts as demonstrated by an increase in the LC3b II/I ratio. Immunostaining of the reconstituted heart showed that the number of LC3b+ cells was 3-fold higher in YP than OP hearts. These LC3b+ cells were both donor and recepiant cells. Conclusions: The increase in autophagy rate in the YP heart suggests that autophagy is one of the mechanisms involved in rejuvenation of the aged heart after BM reconstitution. Y-Sca-1+ BM cells secret factors that improve the autophagy of recepient cardiac cells. [ABSTRACT FROM AUTHOR]
- Published
- 2018
73. Abstract 12105: Human CD34+ Stem Cell Chimerism Pre-Conditions the Heart to Prevent Extensive Remodeling Following Myocardial Infarction.
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Binesh Marvasti, Tina, Alibhai, Faisal J, Li, Shu-Hong, Wu, Jun, Weisel, Richard D, Yau, Terrence M, and Li, Ren-Ke
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HUMAN stem cells , *BONE marrow cells , *MYOCARDIAL infarction , *CHIMERISM , *HEART cells - Abstract
Introduction: Clinical trials of cell therapy for post-injury conditioning of the myocardium have shown only modest improvements, perhaps because the majority of donor cells die in the harsh post-ischemic environment. Hypothesis: We hypothesize that pre-conditioning the myocardium by delivering human CD34+ (hCD34+) cells through bone marrow (BM) engraftment may prevent adverse remodeling and heart failure post myocardial infarct (MI). BM engraftment may be especially important in elderly patients because of their reduced stem cell function. Methods: BM aspirates from 40 patients undergoing open-heart surgery were collected. Mononuclear cells were isolated and stem cell subpopulations were quantified using flow cytometry and magnetically sorted. Function of hCD34+ cells was analyzed by the colony forming unit (CFU) assay and their ability to reconstitute irradiated immune-deficient NSG mice. Engraftment was quantified as hCD45 chimerism by flow cytometry. To evaluate the benefits of hCD34+ cells in cardiac repair, coronary artery ligation was performed 12 weeks post-reconstitution. Left ventricular (LV) function and histology were assessed by echocardiography and immunohistochemistry. Results: Older patients (>60 years old, n=24) had lower numbers (p=0.0008) and reduced function (p<0.0001) of hCD34+ cells. We found a significant difference in the homing ability of hCD34+ (n=7) vs. hCD34- (n=6) cells to the bone marrow, blood, spleen and heart (p<0.05, all groups) 12 weeks post-reconstitution. hCD34+ mice engrafted with young patients' cells had higher reconstitution in blood, spleen and heart (p<0.01, all groups). At 4 weeks post-ligation, hCD34+ mice (n=8) had improved LV function, with greater fractional shortening (p=0.003), reduced LV dilation (p=0.02) and reduced scar size (p=0.0002). Immunohistochemistry of the peri-infarct region of CD34+ mice showed increased hCD34-derived vessels, indicating their role in infarct healing. Conclusions: hCD34+ cells have reduced frequency and function in older patients, but engraft and protect the myocardium from functional decline post-MI. Cardiac pre-conditioning by restoration of aged hCD34+ cells is a promising avenue for preventing cardiac dysfunction post-MI. [ABSTRACT FROM AUTHOR]
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- 2018
74. Young Bone-Marrow Sca-1+ Stem Cells Rejuvenate the Aged Heart and Improve Function after Injury through PDGFRβ-Akt pathway.
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Li, Shu-Hong, Sun, Lu, Yang, Lei, Li, Jiao, Shao, Zhengbo, Du, Guo-Qing, Wu, Jun, Weisel, Richard D., and Li, Ren-Ke
- Abstract
Bone marrow (BM) reconstitution with young BM cells in aged recipients restores the functionality of cardiac resident BM-derived progenitors. This study investigated the cell type primarily responsible for this effect. We reconstituted old mice with BM cells from young or old mice and found that the number of stem cell antigen 1 (Sca-1) cells homing to the heart was significantly greater in young than old chimeras. We then reconstituted old mice with young BM Sca-1+ or Sca-1− cells. We found that Sca-1 cells repopulated the recipient BM and homed to the heart. The number of BM-derived cells in the aged myocardium co-expressing PDGFRβ was 3 times greater in Sca-1+ than Sca-1− chimeric mice. Sca-1+ chimeras had more active cell proliferation in the infarcted heart and improved ventricular function after MI. The improved regeneration involved activation of the PDGFRβ/Akt/p27Kip1 pathway. Sca-1+ stem cells rejuvenated cardiac tissue in aged mice. Restoration of the Sca-1+ subset of stem cells by BM reconstitution improved cardiac tissue regeneration after injury in aged mice. [ABSTRACT FROM AUTHOR]
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- 2017
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75. Joint statement on redundant (duplicate) publication by the Editors of the undersigned cardio-thoracic journals.
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Kumar, A. Sampath, Beyersdorf, Friedhelm, Denniss, A. Robert, Lazar, Harold L., Patterson, G. Alexander, and Weisel, Richard D.
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PERIODICAL publishing , *ETHICS , *INFORMATION sharing , *ELECTRONIC information resource searching , *HEART - Abstract
The article discusses the joint statement of periodical editors on how to address duplicate publication in undersigned cardio-thoracic journals. Topics mentioned include the key reasons why redundant or duplicate publication is unethical, the use of electronic search applications and information exchange to prevent redundant publication, and the key defining elements of redundant publication.
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- 2015
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76. L-arginine protects human heart cells from simulated anoxia and reoxgenation
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Verma, Subodh, Shiono, Noritsugu, Li, Ren-Ke, Mickle, Donald A., Fedak, Paul W., and Weisel, Richard D.
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- 2002
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77. Bosentan: a therapeutic strategy for severe radial artery vasospasm
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Verma, Subodh, Hyder, Tara, Ko, Lawrence, Badiwala, Mitesh V., Fedak, Paul, Li, Ren-Ke, Weisel, Richard D., Rao, Vivek, and Fremes, Stephen E.
- Published
- 2002
- Full Text
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