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Brian R Walker - One of the best experts on this subject based on the ideXlab platform.

  • 11β hsd1 suppresses cardiac fibroblast cxcl2 cxcl5 and neutrophil recruitment to the heart post mi
    Journal of Endocrinology, 2017
    Co-Authors: Katie J Mylonas, Sumia A Bageghni, Christopher I White, Kieran Mcgregor, Robert A Kimmitt, Richard Sulston, Valerie Kelly, Neil A Turner, Christopher J Kenyon, Brian R Walker
    Abstract:

    We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1(-)(/)(-) ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from Host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'Host' Myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the Myocardium of Hsd11b1(-)(/)(-) mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1(-)(/)(-) mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5 These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured Myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

  • 11β hsd1 suppresses cardiac fibroblast cxcl2 cxcl5 and neutrophil recruitment to the heart post mi
    Journal of Endocrinology, 2017
    Co-Authors: Katie J Mylonas, Sumia A Bageghni, Christopher I White, Kieran Mcgregor, Robert A Kimmitt, Richard Sulston, Valerie Kelly, Neil A Turner, Christopher J Kenyon, Brian R Walker
    Abstract:

    We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1(-)(/)(-) ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from Host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'Host' Myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the Myocardium of Hsd11b1(-)(/)(-) mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1(-)(/)(-) mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5 These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured Myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

Charles E. Murry - One of the best experts on this subject based on the ideXlab platform.

  • enhanced electrical integration of engineered human Myocardium via intramyocardial versus epicardial delivery in infarcted rat hearts
    PLOS ONE, 2015
    Co-Authors: Kaytlyn A. Gerbin, Charles E. Murry, Xiulan Yang, Kareen L. K. Coulombe
    Abstract:

    Cardiac tissue engineering is a promising approach to provide large-scale tissues for transplantation to regenerate the heart after ischemic injury, however, integration with the Host Myocardium will be required to achieve electromechanical benefits. To test the ability of engineered heart tissues to electrically integrate with the Host, 10 million human embryonic stem cell (hESC)-derived cardiomyocytes were used to form either scaffold-free tissue patches implanted on the epicardium or micro-tissue particles (~1000 cells/particle) delivered by intramyocardial injection into the left ventricular wall of the ischemia/reperfusion injured athymic rat heart. Results were compared to intramyocardial injection of 10 million dispersed hESC-cardiomyocytes. Graft size was not significantly different between treatment groups and correlated inversely with infarct size. After implantation on the epicardial surface, hESC-cardiac tissue patches were electromechanically active, but they beat slowly and were not electrically coupled to the Host at 4 weeks based on ex vivo fluorescent imaging of their graft-autonomous GCaMP3 calcium reporter. Histologically, scar tissue physically separated the patch graft and Host Myocardium. In contrast, following intramyocardial injection of micro-tissue particles and suspended cardiomyocytes, 100% of the grafts detected by fluorescent GCaMP3 imaging were electrically coupled to the Host heart at spontaneous rate and could follow Host pacing up to a maximum of 300–390 beats per minute (5–6.5 Hz). Gap junctions between intramyocardial graft and Host tissue were identified histologically. The extensive coupling and rapid response rate of the human myocardial grafts after intramyocardial delivery suggest electrophysiological adaptation of hESC-derived cardiomyocytes to the rat heart’s pacemaking activity. These data support the use of the rat model for studying electromechanical integration of human cardiomyocytes, and they identify lack of electrical integration as a challenge to overcome in tissue engineered patches.

  • Intramyocardial implants have connexin 43-positive junctions with Host cardiomyocytes.
    2015
    Co-Authors: Kaytlyn A. Gerbin, Charles E. Murry, Xiulan Yang, Kareen L. K. Coulombe
    Abstract:

    Evidence of connexin 43-positive gap junction formation between Host cardiomyocytes and hESC-cardiomyocyte grafts was found for cell grafts (A) and micro-tissue particle grafts (B). Boxed region in left column is shown at 4-fold magnification in the right column, highlighting the junctions between graft and Host (white arrow heads). Patch implants showed connexin 43-positive regions within the patch (boxed region and right column) and no evidence of gap junction formation with the Host, as hESC-cardiomyocytes were physically separated from the Host Myocardium by scar tissue (C). g, graft; s, scar, h, Host. Scale bar = 50 μm.

  • Human grafts contain striated cardiomyocytes.
    2015
    Co-Authors: Kaytlyn A. Gerbin, Charles E. Murry, Xiulan Yang, Kareen L. K. Coulombe
    Abstract:

    Confocal fluorescent imaging of engrafted hESC-cardiomyocytes at 4 weeks indicate that all three engraftment methods produce grafts that have high cardiac purity, as indicated by a double-positive stain for α-actinin (red) and GFP (green) with nuclear DAPI (blue), in representative images of all grafts. All grafts demonstrate sarcomere striations at higher magnification (far right). Scar tissue appears as the dark band separating the patch graft and Host Myocardium (see Fig 3 for picrosirius red labeled scar, black arrowhead) and this extends to the edges of the patch (outside the field of view; not shown). White arrowhead in patch image points to GFP+/α-actinin- non-cardiac cells. g, graft; s, scar, h, Host. Scale bar = 500 μm and 50 μm (far right column).

  • growth of engineered human Myocardium with mechanical loading and vascular coculture
    Circulation Research, 2011
    Co-Authors: Nathaniel L Tulloch, Kip D Hauch, Hans Reinecke, Veronica Muskheli, Maria V Razumova, Steven F Korte, Michael Regnier, Lil Pabon, Charles E. Murry
    Abstract:

    Rationale: The developing heart requires both mechanical load and vascularization to reach its proper size, yet the regulation of human heart growth by these processes is poorly understood. Objective: We seek to elucidate the responses of immature human Myocardium to mechanical load and vascularization using tissue engineering approaches. Methods and Results: Using human embryonic stem cell and human induced pluripotent stem cell–derived cardiomyocytes in a 3-dimensional collagen matrix, we show that uniaxial mechanical stress conditioning promotes 2-fold increases in cardiomyocyte and matrix fiber alignment and enhances myofibrillogenesis and sarcomeric banding. Furthermore, cyclic stress conditioning markedly increases cardiomyocyte hypertrophy (2.2-fold) and proliferation rates (21%) versus unconditioned constructs. Addition of endothelial cells enhances cardiomyocyte proliferation under all stress conditions (14% to 19%), and addition of stromal supporting cells enhances formation of vessel-like structures by ≈10-fold. Furthermore, these optimized human cardiac tissue constructs generate Starling curves, increasing their active force in response to increased resting length. When transplanted onto hearts of athymic rats, the human Myocardium survives and forms grafts closely apposed to Host Myocardium. The grafts contain human microvessels that are perfused by the Host coronary circulation. Conclusions: Our results indicate that both mechanical load and vascular cell coculture control cardiomyocyte proliferation, and that mechanical load further controls the hypertrophy and architecture of engineered human Myocardium. Such constructs may be useful for studying human cardiac development as well as for regenerative therapy. # Novelty and Significance {#article-title-70}

  • proangiogenic scaffolds as functional templates for cardiac tissue engineering
    Proceedings of the National Academy of Sciences of the United States of America, 2010
    Co-Authors: Lauran R Madden, Charles E. Murry, Derek J Mortisen, Eric M Sussman, Sarah K Dupras, James A Fugate, Kip D Hauch, Michael A Laflamme, Buddy D. Ratner
    Abstract:

    We demonstrate here a cardiac tissue-engineering strategy addressing multicellular organization, integration into Host Myocardium, and directional cues to reconstruct the functional architecture of heart muscle. Microtemplating is used to shape poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogel into a tissue-engineering scaffold with architectures driving heart tissue integration. The construct contains parallel channels to organize cardiomyocyte bundles, supported by micrometer-sized, spherical, interconnected pores that enhance angiogenesis while reducing scarring. Surface-modified scaffolds were seeded with human ES cell-derived cardiomyocytes and cultured in vitro. Cardiomyocytes survived and proliferated for 2 wk in scaffolds, reaching adult heart densities. Cardiac implantation of acellular scaffolds with pore diameters of 30–40 μm showed angiogenesis and reduced fibrotic response, coinciding with a shift in macrophage phenotype toward the M2 state. This work establishes a foundation for spatially controlled cardiac tissue engineering by providing discrete compartments for cardiomyocytes and stroma in a scaffold that enhances vascularization and integration while controlling the inflammatory response.

Jacqueline S. Wendel - One of the best experts on this subject based on the ideXlab platform.

  • Functional Effects of a Tissue-Engineered Cardiac Patch From Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Rat Infarct Model
    Stem cells translational medicine, 2015
    Co-Authors: Jacqueline S. Wendel, Ran Tao, Jianyi Zhang, Jianhua Zhang, Timothy J. Kamp, Robert T. Tranquillo
    Abstract:

    A tissue-engineered cardiac patch provides a method to deliver cardiomyoctes to the injured Myocardium with high cell retention and large, controlled infarct coverage, enhancing the ability of cells to limit remodeling after infarction. The patch environment can also yield increased survival. In the present study, we sought to assess the efficacy of a cardiac patch made from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to engraft and limit left ventricular (LV) remodeling acutely after infarction. Cardiac patches were created from hiPSC-CMs and human pericytes (PCs) entrapped in a fibrin gel and implanted acutely onto athymic rat hearts. hiPSC-CMs not only remained viable after in vivo culture, but also increased in number by as much as twofold, consistent with colocalization of human nuclear antigen, cardiac troponin T, and Ki-67 staining. CM+PC patches led to reduced infarct sizes compared with myocardial infarction-only controls at week 4, and CM+PC patch recipient hearts exhibited greater fractional shortening over all groups at both 1 and 4 weeks after transplantation. However, a decline occurred in fractional shortening for all groups over 4 weeks, and LV thinning was not mitigated. CM+PC patches became vascularized in vivo, and microvessels were more abundant in the Host Myocardium border zone, suggesting a paracrine mechanism for the improved cardiac function. PCs in a PC-only control patch did not survive 4 weeks in vivo. Our results indicate that cardiac patches containing hiPSC-CMs engraft onto acute infarcts, and the hiPSC-CMs survive, proliferate, and contribute to a reduction in infarct size and improvements in cardiac function.

  • functional consequences of a tissue engineered myocardial patch for cardiac repair in a rat infarct model
    Tissue Engineering Part A, 2014
    Co-Authors: Jacqueline S. Wendel, Pengyuan Zhang, Robert T. Tranquillo, Jianyi Jay Zhang
    Abstract:

    Cell therapies have emerged as a promising treatment for the prevention of heart failure after myocardial infarction (MI). This study evaluated the capacity of an aligned, fibrin-based, stretch-conditioned cardiac patch consisting of either the native population or a cardiomyocyte (CM)-depleted population (i.e., CM+ or CM- patches) of neonatal rat heart cells to ameliorate left ventricular (LV) remodeling in the acute-phase postinfarction in syngeneic, immunocompetent rats. Patches were exposed to 7 days of static culture and 7 days of cyclic stretching prior to implantation. Within 1 week of implantation, both patches became vascularized, and non-CMs began migrating from CM+ patches. By week 4, patches had been remodeled into collagenous tissue, and live, elongated, donor CMs were found within grafted CM+ patches. Significant improvement in cardiac contractile function was seen with the administration of the CM+ patch (ejection fraction increased from 35.1% ± 4.0% for MI only to 58.8% ± 7.3% with a CM+ patch, p<0.05) associated with a 77% reduction in infarct size (61.3% ± 7.9% for MI only, 13.9% ± 10.8% for CM+ patch, p<0.05), and the elimination of LV free-wall thinning. Decreased infarct size and reduced wall thinning also occurred with the administration of the CM- patch (infarct size 36.9% ± 10.2%, LV wall thickness: 1058.2 ± 135.4 μm for CM- patch, 661.3 ± 37.4 μm for MI only, p<0.05), but without improvements in cardiac function. Approximately 36.5% of the transplanted CMs survived at 4 weeks; however, they remained separated and electrically uncoupled from the Host Myocardium by a layer of CM-free tissue, which suggests that the benefits of CM+ patch transplantation resulted from paracrine mechanisms originating from CMs. Collectively, these observations suggest that the transplantation of CM-containing engineered heart tissue patches can lead to dramatic improvements in cardiac function and remodeling after acute MI.

  • Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells
    Cell Stem Cell, 2014
    Co-Authors: Lei Ye, Ying Hua Chang, Mike Lepley, Cory Swingen, Porur Somasundaram, Qiang Xiong, Pengyuan Zhang, Liping Su, Liying Zhang, Jacqueline S. Wendel
    Abstract:

    Human induced pluripotent stem cells (hiPSCs) hold promise for myocardial repair following injury, but preclinical studies in large animal models are required to determine optimal cell preparation and delivery strategies to maximize functional benefits and to evaluate safety. Here, we utilized a porcine model of acute myocardial infarction (MI) to investigate the functional impact of intramyocardial transplantation of hiPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells, in combination with a 3D fibrin patch loaded with insulin growth factor (IGF)-encapsulated microspheres. hiPSC-derived cardiomyocytes integrated into Host Myocardium and generated organized sarcomeric structures, and endothelial and smooth muscle cells contributed to Host vasculature. Trilineage cell transplantation significantly improved left ventricular function, myocardial metabolism, and arteriole density, while reducing infarct size, ventricular wall stress, and apoptosis without inducing ventricular arrhythmias. These findings in a large animal MI model highlight the potential of utilizing hiPSC-derived cells for cardiac repair.

Katie J Mylonas - One of the best experts on this subject based on the ideXlab platform.

  • 11β hsd1 suppresses cardiac fibroblast cxcl2 cxcl5 and neutrophil recruitment to the heart post mi
    Journal of Endocrinology, 2017
    Co-Authors: Katie J Mylonas, Sumia A Bageghni, Christopher I White, Kieran Mcgregor, Robert A Kimmitt, Richard Sulston, Valerie Kelly, Neil A Turner, Christopher J Kenyon, Brian R Walker
    Abstract:

    We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1(-)(/)(-) ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from Host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'Host' Myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the Myocardium of Hsd11b1(-)(/)(-) mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1(-)(/)(-) mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5 These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured Myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

  • 11β hsd1 suppresses cardiac fibroblast cxcl2 cxcl5 and neutrophil recruitment to the heart post mi
    Journal of Endocrinology, 2017
    Co-Authors: Katie J Mylonas, Sumia A Bageghni, Christopher I White, Kieran Mcgregor, Robert A Kimmitt, Richard Sulston, Valerie Kelly, Neil A Turner, Christopher J Kenyon, Brian R Walker
    Abstract:

    We have previously demonstrated that neutrophil recruitment to the heart following myocardial infarction (MI) is enhanced in mice lacking 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) that regenerates active glucocorticoid within cells from intrinsically inert metabolites. The present study aimed to identify the mechanism of regulation. In a mouse model of MI, neutrophil mobilization to blood and recruitment to the heart were higher in 11β-HSD1-deficient (Hsd11b1(-)(/)(-) ) relative to wild-type (WT) mice, despite similar initial injury and circulating glucocorticoid. In bone marrow chimeric mice, neutrophil mobilization was increased when 11β-HSD1 was absent from Host cells, but not when absent from donor bone marrow-derived cells. Consistent with a role for 11β-HSD1 in 'Host' Myocardium, gene expression of a subset of neutrophil chemoattractants, including the chemokines Cxcl2 and Cxcl5, was selectively increased in the Myocardium of Hsd11b1(-)(/)(-) mice relative to WT. SM22α-Cre directed disruption of Hsd11b1 in smooth muscle and cardiomyocytes had no effect on neutrophil recruitment. Expression of Cxcl2 and Cxcl5 was elevated in fibroblast fractions isolated from hearts of Hsd11b1(-)(/)(-) mice post MI and provision of either corticosterone or of the 11β-HSD1 substrate, 11-dehydrocorticosterone, to cultured murine cardiac fibroblasts suppressed IL-1α-induced expression of Cxcl2 and Cxcl5 These data identify suppression of CXCL2 and CXCL5 chemoattractant expression by 11β-HSD1 as a novel mechanism with potential for regulation of neutrophil recruitment to the injured Myocardium, and cardiac fibroblasts as a key site for intracellular glucocorticoid regeneration during acute inflammation following myocardial injury.

Lingjun Wang - One of the best experts on this subject based on the ideXlab platform.

  • transplantation of isl1 cardiac progenitor cells in small intestinal submucosa improves infarcted heart function
    Stem Cell Research & Therapy, 2017
    Co-Authors: Lingjun Wang, Elizabeth M Meier, Shuo Tian, Shaoxiang Xian, Zhong Wang
    Abstract:

    Application of cardiac stem cells combined with biomaterial scaffold is a promising therapeutic strategy for heart repair after myocardial infarction. However, the optimal cell types and biomaterials remain elusive. In this study, we seeded Isl1+ embryonic cardiac progenitor cells (CPCs) into decellularized porcine small intestinal submucosa extracellular matrix (SIS-ECM) to assess the therapeutic potential of Isl1+ CPCs and the biocompatibility of SIS-ECM with these cells. We observed that SIS-ECM supported the viability and attachment of Isl1+ CPCs. Importantly, Isl1+ CPCs differentiated into cardiomyocytes and endothelial cells 7 days after seeding into SIS-ECM. In addition, SIS-ECM with CPC-derived cardiomyocytes showed spontaneous contraction and responded to β-adrenergic stimulation. Next, patches of SIS-ECM seeded with CPCs for 7 days were transplanted onto the outer surface of infarcted Myocardium in mice. Four weeks after transplantation, the patches were tightly attached to the surface of the Host Myocardium and remained viable. Transplantation of patches improved cardiac function, decreased the left ventricular myocardial scarring area, and reduced fibrosis and heart failure. Transplantation of Isl1+ CPCs seeded in SIS-ECM represents an effective approach for cell-based heart therapy.