ORCID Profile
0000-0002-3689-4275
Current Organisations
Kolling Institute of Medical Research
,
Harvard Medical School
,
University of Sydney
,
University of Technology Sydney
,
KU Leuven
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Nanomanufacturing | Nanomaterials | Nanotechnology | Microtechnology
Expanding Knowledge in the Physical Sciences | Expanding Knowledge in Engineering | Expanding Knowledge in the Medical and Health Sciences |
Publisher: Center for Open Science
Date: 02-02-2021
Abstract: BACKGROUND: 3D bioprinting cardiac patches for epicardial transplantation is a promising approach for myocardial regeneration. Challenges remain such as quantifying printability, determining the ideal moment to transplant and promoting vascularisation within bioprinted patches. We aimed to evaluate 3D bioprinted cardiac patches for printability, durability in culture, cell viability and endothelial cell structural self-organisation into networks. METHODS: We evaluated 3D-bioprinted double-layer patches using alginate/gelatine (AlgGel) hydrogels and three extrusion bioprinters (REGEMAT3D INVIVO BIO X). Bioink contained either neonatal mouse cardiac cell spheroids or free (not-in-spheroid) human coronary artery endothelial cells with fibroblasts, mixed with AlgGel. To test effects on durability, some patches were bioprinted as a single layer only, cultured under minimal movement conditions or had added fibroblast-derived extracellular matrix hydrogel (AlloECM). Controls included acellular AlgGel and gelatin methacryloyl (GELMA) patches. RESULTS: Printability was similar across bioprinters. For AlgGel compared to GELMA: resolutions were similar (200-700μm line diameters), printing accuracy was 45% and 25%, respectively (AlgGel was 1.7x more accurate & .05), shape fidelity was 92% (AlgGel) and 96% (GELMA) =0.36. For durability, AlgGel patch median survival in culture was 14 days (IQR:10-27) overall which was not significantly affected by bioprinting system or cellular content in patches. We identified three factors which reduced durability in culture: 1) bioprinting one layer depth patches (instead of two layers) 2) movement disturbance to patches in media 3) the addition of AlloECM to AlgGel. Cells were viable after bioprinting followed by 28 days in culture and all BIO X-bioprinted mouse cardiac cell spheroid patches presented contractile activity starting between day 7 and 13 after bioprinting. At day 28, endothelial cells in hydrogel displayed organisation into endothelial network-like structures. CONCLUSIONS: AlgGel-based 3D bioprinted heart patches permit cardiomyocyte contractility and endothelial cell structural self-organisation. After bioprinting, a period of 2 weeks' maturation in culture prior to transplantation may be optimal, allowing for a degree of tissue maturation but before many patches start to lose integrity. We quantify AlgGel printability and present novel factors which reduce AlgGel patch durability (layer number, movement and the addition of AlloECM) and factors which had minimal effect on durability (bioprinting system and cellular patch content).
Publisher: Elsevier BV
Date: 12-2022
Publisher: Frontiers Media SA
Date: 06-09-2021
Publisher: MDPI AG
Date: 25-02-2022
DOI: 10.3390/BIOENGINEERING9030093
Abstract: Despite a massive global preventative effort, heart failure remains the major cause of death globally. The number of patients requiring a heart transplant, the eventual last treatment option, far outnumbers the available donor hearts, leaving many to deteriorate or die on the transplant waiting list. Treating heart failure by transplanting a 3D bioprinted patient-specific cardiac patch to the infarcted region on the myocardium has been investigated as a potential future treatment. To date, several studies have created cardiac patches using 3D bioprinting however, testing the concept is still at a pre-clinical stage. A handful of clinical studies have been conducted. However, moving from animal studies to human trials will require an increase in research in this area. This review covers key elements to the design of a patient-specific cardiac patch, ided into general areas of biological design and 3D modelling. It will make recommendations on incorporating anatomical considerations and high-definition motion data into the process of 3D-bioprinting a patient-specific cardiac patch.
Publisher: Wiley
Date: 22-01-2010
DOI: 10.1002/DVDY.22161
Publisher: Research Square Platform LLC
Date: 30-12-2020
DOI: 10.21203/RS.3.RS-135799/V1
Abstract: Background: Preecl sia is a life-threatening cardiovascular disorder of pregnancy that leads to an increased risk of ongoing cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preecl sia and cardiovascular disease (CVD). Therefore, in this study we aimed to investigate the role of FKBPL in cardiac health in the rat reduced uterine perfusion pressure (RUPP) model and 3D cardiac spheroid model, of preecl sia. Methods: The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidneys, liver and placenta (n≥6). Picrosirius red staining was performed to quantify collagen I/III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl , Icam1 , Vcam1, Flt1 and/or Vegfa mRNA in hearts and/or placentae and ELISA was used to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion in rat hearts. Cardiac spheroids were generated using human cardiac fibroblasts (HCFs) and human coronary artery endothelial cells (HCAECs) and treated with patient plasma from normotensive controls, early-onset preecl sia (EOPE) and late-onset preecl sia (LOPE) (n=3). FKBPL and CD31 expression was quantified by immunofluorescent labelling. Results: The RUPP procedure induced significant increase in blood pressure (p .001), cardiac collagen deposition (p .001) and cardiac BNP45 (p .05). It also induced a significant increase in cardiac FKBPL mRNA expression (p .05) and protein levels (p .01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p .05). RUPP kidneys revealed an increase in average glomerular size (p .05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE patient plasma (p .05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p=0.06). Conclusions: The rat RUPP model induced cardiac, renal and placental features reflective of preecl sia in humans. FKBPL was increased in the hearts of RUPP rats and in cardiac spheroids treated with plasma from women with preecl sia, reflective of restricted angiogenesis in this disorder. Elucidation of this novel FKBPL mechanism in cardiac health in preecl sia could be key in preventing future CVD.
Publisher: IOP Publishing
Date: 15-09-2023
Abstract: Spheroids are microtissues containing cells organized in a spherical shape whose diameter is usually less than a millimetre. Depending on the properties of the environment they are placed in, some nearby spheroids spontaneously fuse and generate a tissue. Given their potential to mimic features typical of body parts and their ability to assemble by fusing in permissive hydrogels, they have been used as building blocks to 3D bioprint human tissue parts. Parameters controlling the shape and size of a bioprinted tissue using fusing spheroid cultures include cell composition, hydrogel properties, and their relative initial position. Hence, simulating, anticipating, and then controlling the spheroid fusion process is essential to control the shape and size of the bioprinted tissue.& #xD & #xD This study presents the first physically-based framework to simulate the fusion process of bioprinted spheroids. The simulation is based on elastic-plastic solid and fluid continuum mechanics models. Both models use the “smoothed particle hydrodynamics” (SPH) method, which is based on discretizing the continuous medium into a finite number of particles and solving the differential equations related to the physical properties (e.g., Navier-Stokes equation) using a smoothing kernel function.& #xD & #xD To further investigate the effects of such parameters on spheroid shape and geometry, we performed sensitivity and morphological analysis to validate our simulations with in-vitro spheroids. Through our in-silico simulations by changing the aforementioned parameters, we show that the proposed models appropriately simulate the range of the elastic-plastic behaviours of in-vitro fusing spheroids to generate tissues of desired shapes and sizes.& #xD & #xD Altogether, this study presented a physically-based simulation that can provide a framework for monitoring and controlling the geometrical shape of spheroids, directly impacting future research using spheroids for tissue bioprinting.
Publisher: Wiley
Date: 16-03-2010
DOI: 10.1002/DVDY.22286
Publisher: Elsevier BV
Date: 2022
Publisher: Georg Thieme Verlag KG
Date: 04-2022
Publisher: Frontiers Media SA
Date: 20-06-2022
Abstract: Myocardial infarction (MI, or heart attack) is a leading cause of death worldwide. Myocardial ischaemia reperfusion (I/R) injury typical of MI events is also associated with the development of cardiac fibrosis and heart failure in patients. Fibulin-3 is an extracellular matrix component that plays a role in regulating MI response in the heart. In this study, we generated and compared in vitro cardiac spheroids (CSs) from wild type (WT) and fibulin-3 knockout (Fib-3 KO) mice. These were then exposed to pathophysiological changes in oxygen (O 2 ) concentrations to mimic an MI event. We finally measured changes in contractile function, cell death, and mRNA expression levels of cardiovascular disease genes between WT and Fib-3 KO CSs. Our results demonstrated that there are significant differences in growth kinetics and endothelial network formation between WT and Fib-3 KO CSs, however, they respond similarly to changes in O 2 concentrations. Fib-3 deficiency resulted in an increase in viability of cells and improvement in contraction frequency and fractional shortening compared to WT I/R CSs. Gene expression analyses demonstrated that Fib-3 deficiency inhibits I/R injury and cardiac fibrosis and promotes angiogenesis in CSs. Altogether, our findings suggest that Fib-3 deficiency makes CSs resistant to I/R injury and associated cardiac fibrosis and helps to improve the vascular network in CSs.
Publisher: MedCrave Group, LLC
Date: 08-06-2017
Publisher: Georg Thieme Verlag KG
Date: 08-2023
DOI: 10.1055/A-2127-4436
Publisher: Elsevier BV
Date: 11-2014
Publisher: Oxford University Press (OUP)
Date: 07-05-2021
Publisher: Elsevier BV
Date: 2013
Publisher: MyJove Corporation
Date: 26-09-2020
DOI: 10.3791/61675
Publisher: MDPI AG
Date: 30-10-2023
Publisher: Wiley
Date: 04-07-2023
Abstract: Nature abounds with micro‐architected materials containing layered multi‐material patterns that often transition within the very same monolithic piece. Fabricating these complex materials using current technologies is challenging. Multimaterial chaotic printing is presented—an extrusive printing method based on the use of chaotic advection—that can fabricate microstructured hydrogels with well‐defined multimaterial and multilayered micropatterns. Printheads containing internal Kenics static mixing (KSM) elements and top‐ and lateral‐positioned inlets are used to produce a wide repertoire of multilayered hydrogel filaments. In this plug‐and‐play system, the radial and axial micropatterns can be designed ad hoc by defining the printhead configuration (i.e., the number of KSM elements and inlets, and the inlet positions) and the flow program (i.e., activation/deactivation of the ink‐flow through each inlet). Computational fluid dynamics simulations closely predict the microstructure obtained by a given printhead configuration. The application of this platform is illustrated for easy fabrication of fibers with radial microgradients, bacterial ecosystems, structured emulsions, micro‐channeled hydrogel filaments, a pre‐vascularized tumor niche model, and skeletal muscle‐like tissues with axial and radial transitions of bioactive glass compartments. It is envisioned that multimaterial chaotic printing will be a valuable addition to the toolbox of additive manufacturing for the rational fabrication of advanced materials.
Publisher: Wiley
Date: 09-2023
Publisher: Elsevier BV
Date: 12-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-03-2021
Publisher: Elsevier BV
Date: 03-2021
Publisher: Wiley
Date: 19-01-2021
Abstract: Despite the latest advances in cardiovascular biology and medicine, myocardial infarction (MI) remains one of the major causes of deaths worldwide. While reperfusion of the myocardium is critical to limit the ischemic damage typical of a MI event, it causes detrimental morphological and functional changes known as “reperfusion injury.” This complex scenario is poorly represented in currently available models of ischemia/reperfusion injury, leading to a poor translation of findings from the bench to the bedside. However, more recent bioengineered in vitro models of the human heart represent more clinically relevant tools to prevent and treat MI in patients. These include 3D cultures of cardiac cells, the use of patient‐derived stem cells, and 3D bioprinting technology. This review aims at highlighting the major features typical of a heart attack while comparing current in vitro, ex vivo, and in vivo models. This information has the potential to further guide in developing novel advanced in vitro cardiac models of ischemia/reperfusion injury. It may pave the way for the generation of advanced pathophysiological cardiac models with the potential to develop personalized therapies.
Publisher: Wiley
Date: 28-03-2023
DOI: 10.1111/APT.17463
Abstract: Long‐term administration of TDF/ETV in patients with HBV‐related compensated cirrhosis reduces HCC and decompensation events but the effect of this regimen on development/regression of oesophageal varices (EV) is currently unknown. To assess the risk of EV development rogression in this population. A total of 186 Caucasian HBV‐monoinfected compensated cirrhotics were enrolled in a long‐term cohort study from TDF/ETV introduction. Upper GI endoscopies were performed according to Baveno recommendations. Primary endpoint was development rogression of oesophageal/gastric varices over time. At TDF/ETV start, median age was 61 years, 80% males, 60% HBV‐DNA undetectable, 63% NUCs previously exposed, 73% normal ALT, 40% platelets ,000/mmc and 25 (13%) with low‐risk varices (LRV). During 11 years of antiviral therapy and 666 endoscopies performed, 9 patients either developed or had a progression of oesophageal or gastric varices with an 11‐year cumulative probability of 5.1% (95% CI 3–10%) no patient bled. Out of 161 patients without EV at baseline, the 11‐year probably was 4.5% with all varices developing within the first six years of treatment. In 25 patients with LRV at baseline, the 11‐year probability of progression or regression was 9.3% and 58%, respectively. Only baseline platelet count (HR 0.96, p = 0.028) was associated with LRV development at multivariate analysis: platelet ≤90,000/mmc (AUROC 0.70) had 98.1% specificity, 42.9% sensitivity, 50% PPV for LRV onset. In compensated cirrhotic patients under long‐term effective TDF/ETV treatment, the 11‐year risk of developing rogressing EV is negligible, thus challenging the current endoscopic surveillance recommendations in patients without EV at baseline.
Publisher: Oxford University Press (OUP)
Date: 18-08-2020
Abstract: Preclinical in vivo studies using omental tissue as a biomaterial for myocardial regeneration are promising and have not previously been collated. We aimed to evaluate the effects of the omentum as a support for bioengineered tissue therapy for cardiac regeneration in vivo. A systematic scoping review was performed. Only English-language studies that used bioengineered cardio-regenerative tissue, omentum and ischaemic cardiomyopathy in vivo models were included. We initially screened 1926 studies of which 17 were included in the final qualitative analysis. Among these, 11 were methodologically comparable and 6 were non-comparable. The use of the omentum improved the engraftment of bioengineered tissue by improving cell retention and reducing infarct size. Vascularization was also improved by the induction of angiogenesis in the transplanted tissue. Omentum-supported bioengineered grafts were associated with enhanced host reverse remodelling and improved haemodynamic measurements. The omentum is a promising support for myocardial regenerative bioengineering in vivo. Future studies would benefit from more homogenous methodologies and reporting of outcomes to allow for direct comparison.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Frontiers Media SA
Date: 26-02-2021
Publisher: International Association of Physical Chemists (IAPC)
Date: 25-08-2021
DOI: 10.5599/ADMET.951
Abstract: In the last decade, 3D bioprinting technology has emerged as an innovative tissue engineering approach for regenerative medicine and drug development. This article aims at providing an overview about the most commonly used bioengineered tissues, focusing on 3D bioprinted cardiac cells and how they have been utilized for drug discovery and development. The review describes that, while this field is still developing, cardiovascular research may benefit from laboratory-engineered heart tissues built of specific cell types with precise 3D architecture mimicking the native cardiac microenvironment. It also describes the role played by regulatory agencies and potential commercialization pathways for direct translation from the bench to the bedside of studies using 3D bioprinted cardiac tissues. ©2021 by the authors. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (icenses/by/4.0/).
Publisher: Wiley
Date: 11-02-2010
DOI: 10.1002/DVDY.22257
Publisher: Elsevier
Date: 2022
Publisher: Elsevier BV
Date: 2014
Publisher: Wiley
Date: 04-2011
Publisher: Springer International Publishing
Date: 2022
Publisher: Wiley
Date: 24-09-2008
DOI: 10.1002/DVDY.21720
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-02-2016
Abstract: Perturbed balance between NO and O 2 •− . (ie, NO/redox imbalance) is central in the pathobiology of diabetes‐induced vascular dysfunction. We examined whether stimulation of β 3 adrenergic receptors (β 3 ARs), coupled to endothelial nitric oxide synthase (eNOS) activation, would re‐establish NO/redox balance, relieve oxidative inhibition of the membrane proteins eNOS and Na + ‐K + (NK) pump, and improve vascular function in a new animal model of hyperglycemia. We established hyperglycemia in male White New Zealand rabbits by infusion of S961, a competitive high‐affinity peptide inhibitor of the insulin receptor. Hyperglycemia impaired endothelium‐dependent vasorelaxation by “uncoupling” of eNOS via glutathionylation (eNOS‐GSS) that was dependent on NADPH oxidase activity. Accordingly, NO levels were lower while O 2 •− levels were higher in hyperglycemic rabbits. Infusion of the β 3 AR agonist CL316243 (CL) decreased eNOS‐GSS, reduced O 2 •− , restored NO levels, and improved endothelium‐dependent relaxation. CL decreased hyperglycemia‐induced NADPH oxidase activation as suggested by co‐immunoprecipitation experiments, and it increased eNOS co‐immunoprecipitation with glutaredoxin‐1, which may reflect promotion of eNOS de‐glutathionylation by CL. Moreover, CL reversed hyperglycemia‐induced glutathionylation of the β 1 NK pump subunit that causes NK pump inhibition, and improved K + ‐induced vasorelaxation that reflects enhancement in NK pump activity. Lastly, eNOS‐GSS was higher in vessels of diabetic patients and was reduced by CL, suggesting potential significance of the experimental findings in human diabetes. β 3 AR activation restored NO/redox balance and improved endothelial function in hyperglycemia. β 3 AR agonists may confer protection against diabetes‐induced vascular dysfunction.
Publisher: IOP Publishing
Date: 24-01-2022
Abstract: Current preclinical in vitro and in vivo models of cardiac injury typical of myocardial infarction (MI, or heart attack) and drug induced cardiotoxicity mimic only a few aspects of these complex scenarios. This leads to a poor translation of findings from the bench to the bedside. In this study, we biofabricated for the first time advanced in vitro models of MI and doxorubicin (DOX) induced injury by exposing cardiac spheroids (CSs) to pathophysiological changes in oxygen (O 2 ) levels or DOX treatment. Then, contractile function and cell death was analyzed in CSs in control verses I/R and DOX CSs. For a deeper dig into cell death analysis, 3D rendering analyses and mRNA level changes of cardiac damage-related genes were compared in control verses I/R and DOX CSs. Overall, in vitro CSs recapitulated major features typical of the in vivo MI and drug induced cardiac damages, such as adapting intracellular alterations to O 2 concentration changes and incubation with cardiotoxic drug, mimicking the contraction frequency and fractional shortening and changes in mRNA expression levels for genes regulating sarcomere structure, calcium transport, cell cycle, cardiac remodelling and signal transduction. Taken together, our study supports the use of I/R and DOX CSs as advanced in vitro models to study MI and DOX-induced cardiac damge by recapitulating their complex in vivo scenario.
Publisher: Springer International Publishing
Date: 2017
DOI: 10.1007/978-3-319-69194-7_13
Abstract: The stem cell microenvironment or niche plays a critical role in the regulation of survival, differentiation and behavior of stem cells and their progenies. Recapitulating each aspect of the stem cell niche is therefore essential for their optimal use in in vitro studies and in vivo as future therapeutics in humans. Engineering of optimal conditions for three-dimensional stem cell culture includes multiple transient and dynamic physiological stimuli, such as blood flow and tissue stiffness. Bioprinting and microfluidics technologies, including organs-on-a-chip, are among the most recent approaches utilized to replicate the three-dimensional stem cell niche for human tissue fabrication that allow the integration of multiple levels of tissue complexity, including blood flow. This chapter focuses on the physico-chemical and genetic cues utilized to engineer the stem cell niche and provides an overview on how both bioprinting and microfluidics technologies are improving our knowledge in this field for both disease modeling and tissue regeneration, including drug discovery and toxicity high-throughput assays and stem cell-based therapies in humans.
Publisher: Oxford University Press (OUP)
Date: 11-05-2020
Abstract: Previous attempts in cardiac bioengineering have failed to provide tissues for cardiac regeneration. Recent advances in 3-dimensional bioprinting technology using prevascularized myocardial microtissues as ‘bioink’ have provided a promising way forward. This review guides the reader to understand why myocardial tissue engineering is difficult to achieve and how revascularization and contractile function could be restored in 3-dimensional bioprinted heart tissue using patient-derived stem cells.
Publisher: Wiley
Date: 03-2008
Publisher: IOP Publishing
Date: 13-08-2021
Abstract: Current in vivo and in vitro models fail to accurately recapitulate the human heart microenvironment for biomedical applications. This study explores the use of cardiac spheroids (CSs) to biofabricate advanced in vitro models of the human heart. CSs were created from human cardiac myocytes, fibroblasts and endothelial cells (ECs), mixed within optimal alginate/gelatin hydrogels and then bioprinted on a microelectrode plate for drug testing. Bioprinted CSs maintained their structure and viability for at least 30 d after printing. Vascular endothelial growth factor (VEGF) promoted EC branching from CSs within hydrogels. Alginate/gelatin-based hydrogels enabled spheroids fusion, which was further facilitated by addition of VEGF. Bioprinted CSs contracted spontaneously and under stimulation, allowing to record contractile and electrical signals on the microelectrode plates for industrial applications. Taken together, our findings indicate that bioprinted CSs can be used to biofabricate human heart tissues for long term in vitro testing. This has the potential to be used to study biochemical, physiological and pharmacological features of human heart tissue.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2021
DOI: 10.1186/S13293-021-00376-1
Abstract: Preecl sia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preecl sia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preecl sia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preecl sia. The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta ( n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl , Icam1 , Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preecl sia (EOPE) and late-onset preecl sia (LOPE) n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. The RUPP procedure induced significant increases in blood pressure ( p 0.001), collagen deposition ( p 0.001) and cardiac BNP45 ( p 0.05). It also induced a significant increase in cardiac FKBPL mRNA ( p 0.05) and protein expression ( p 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression ( p 0.05). RUPP kidneys revealed an increase in average glomerular size ( p 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma ( p 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma ( p = 0.06). The rat RUPP model induced cardiac, renal and placental features reflective of preecl sia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preecl sia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preecl sia could be key in preventing future CVD.
Publisher: MyJove Corporation
Date: 23-01-2021
DOI: 10.3791/61962
Publisher: S. Karger AG
Date: 2017
DOI: 10.1159/000477436
Abstract: Spheroid cultures are among the most explored cellular biomaterials used in cardiovascular research, due to their improved integration of biochemical and physiological features of the heart in a defined architectural three-dimensional microenvironment when compared to monolayer cultures. To further explore the potential use of spheroid cultures for research, we engineered a novel in vitro model of the heart with vascularized cardiac spheroids (VCSs), by coculturing cardiac myocytes, endothelial cells, and fibroblasts isolated from dissociated rat neonatal hearts (aged 1-3 days) in hanging drop cultures. To evaluate the validity of VCSs in recapitulating pathophysiological processes typical of the in vivo heart, such as cardiac fibrosis, we then treated VCSs with transforming growth factor beta 1 (TGFβ1), a known profibrotic agent. Our mRNA analysis demonstrated that TGFβ1-treated VCSs present elevated levels of expression of connective tissue growth factor, fibronectin, and TGFβ1 when compared to control cultures. We demonstrated a dramatic increase in collagen deposition following TGFβ1 treatment in VCSs in the PicroSirius Red-stained sections. Doxorubicin, a renowned cardiotoxic and profibrotic agent, triggered apoptosis and disrupted vascular networks in VCSs. Taken together, our findings demonstrate that VCSs are a valid model for the study of the mechanisms involved in cardiac fibrosis, with the potential to be used to investigate novel mechanisms and therapeutics for treating and preventing cardiac fibrosis in vitro.
Publisher: Informa UK Limited
Date: 06-2009
Publisher: MDPI AG
Date: 28-05-2021
DOI: 10.3390/IJMS22115792
Abstract: Interleukin (IL)-33 is a member of the interleukin (IL)-1 family of cytokines linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has a direct effect on human gastric epithelial cells (GES-1), the human gastric adenocarcinoma cell line (AGS), and the gastric carcinoma cell line (NCI-N87) by assessing its role in the regulation of cell proliferation, migration, cell cycle, and apoptosis. Cell cycle regulation was also determined in ex vivo gastric cancer s les obtained during endoscopy and surgical procedures. Cell lines and tissue s les underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assays, migration by wound healing assay, and apoptosis by caspase 3/7 activity assay and annexin V assay. Cell cycle was analyzed by means of propidium iodine assay, and gene expression regulation was assessed by RT-PCR profiling. We found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell lines, and it can stimulate proliferation and reduce apoptosis in normal epithelial cell lines. These effects were also confirmed by the analysis of cell cycle gene expression, which showed a reduced expression of pro-proliferative genes in cancer cells, particularly in genes involved in G0/G1 and G2/M checkpoints. These results were confirmed by gene expression analysis on bioptic and surgical specimens. The aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell-type-dependent manner.
Publisher: Wiley
Date: 04-2021
Publisher: Springer New York
Date: 2018
Abstract: Our laboratory has recently developed a novel three-dimensional in vitro model of the human heart, which we call the vascularized cardiac spheroid (VCS). These better recapitulate the human heart's cellular and extracellular microenvironment compared to the existing in vitro models. To achieve this, human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes, cardiac fibroblasts, and human coronary artery endothelial cells are co-cultured in hanging drop culture in ratios similar to those found in the human heart in vivo. The resulting three-dimensional cellular organization, extracellular matrix, and microvascular network formation throughout the VCS has been shown to mimic the one present in the human heart tissue. Therefore, VCSs offer a promising platform to study cardiac physiology, disease, and pharmacology, as well as bioengineering constructs to regenerate heart tissue.
Publisher: Wiley
Date: 04-2014
Publisher: Elsevier BV
Date: 06-2021
Publisher: Frontiers Media SA
Date: 17-04-2023
Publisher: Elsevier BV
Date: 10-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-08-2019
DOI: 10.1161/RES.125.SUPPL_1.138
Abstract: The loss of regenerative properties in adult cardiomyocytes (CMs) is directly linked to their inability to proliferate. Following an extensive ischaemic event in an aged heart, fibrotic scar formation is the only repair process and eventually heart failure develops. However, molecular and cellular cues in the neonatal heart support that cardiac regeneration is possible in presence of proliferating CMs. Based on previous studies demonstrating that endothelial nitric oxide synthase (eNOS) regulates proliferation in both endothelial cells (ECs) and CMs, we hypothesized that eNOS signaling could play a cardioprotective role. To test our hypothesis, we injected different combinations of co-cultured ECs and CMs in the LV muscle wall of MI mice (permanent LAD ligation). First, injected cells were isolated from either WT or KO eNOS neonatal mice and then co-cultured to form 3D vascularized cardiac spheroids (VCSs), which were eventually transplanted in adult MI mice on the day of the procedure. Control infarcted animals received media-only (vehicle). Other mice received a suspension of co-cultured VCSs in media as follows: i ) WT CMs and ECs ii ) WT CMs and KO ECs iii ) KO CMs and WT ECs. Following 28 days, injection of WT cells increased the ejection fraction (EF%) by 20% compared with control animals (61%±4% and 41%±11%, respectively). When eNOS was absent in either CMs or ECs, the EF% was 40%±5% and 46%±2%, respectively, suggesting that the eNOS-mediated protection is dependent on its presence in both cells. Histological analyses confirmed the presence of WT VCSs in MI mice, contributing to a thicker wall thickness compared to vehicle MI mice. No VCSs were observed in the LV wall when KO cells were injected. Therefore, our results strongly suggest that eNOS may play a major role via both an autocrine (CMs) and paracrine (ECs) mechanism. Current studies are focusing on further evaluating the mechanism(s) for this eNOS-mediated protective role. To our knowledge, this is the first study combining cellular and genetic approaches to evaluate the cardioprotective role of eNOS in the heart. A better understanding of this mechanisms may have significant impact for the development of improved molecular and cell therapeutics (including stem cells) for heart failure patients.
Publisher: Elsevier BV
Date: 11-2016
Publisher: MDPI AG
Date: 28-12-2020
Publisher: MDPI AG
Date: 09-03-2021
Publisher: Elsevier BV
Date: 07-2023
DOI: 10.1016/J.ACTBIO.2022.05.009
Abstract: 3D bioprinting technology has emerged as a tool that promises to revolutionize the biomedical field, including tissue engineering and regeneration. Despite major technological advancements, several challenges remain to be solved before 3D bioprinted tissues could be fully translated from the bench to the bedside. As oxygen plays a key role in aerobic metabolism, which allows energy production in the mitochondria as a consequence, the lack of tissue oxygenation is one of the main limitations of current bioprinted tissues and organs. In order to improve tissue oxygenation, recent approaches have been established for a broad range of clinical applications, with some already applied using 3D bioprinting technologies. Among them, the incorporation of photosynthetic microorganisms, such as microalgae and cyanobacteria, is a promising approach that has been recently explored to generate chimerical plant-animal tissues where, upon light exposure, oxygen can be produced and released in a localized and controlled manner. This review will briefly summarize the state-of-the-art approaches to improve tissue oxygenation, as well as studies describing the use of photosynthetic microorganisms in 3D bioprinting technologies. STATEMENT OF SIGNIFICANCE: : 3D bioprinting technology has emerged as a tool for the generation of viable and functional tissues for direct in vitro and in vivo applications, including disease modeling, drug discovery and regenerative medicine. Despite the latest advancements in this field, suboptimal oxygen delivery to cells before, during and after the bioprinting process limits their viability within 3D bioprinted tissues. This review article first highlights state-of-the-art approaches used to improve oxygen delivery in bioengineered tissues to overcome this challenge. Then, it focuses on the emerging roles played by photosynthetic organisms as novel biomaterials for bioink generation. Finally, it provides considerations around current challenges and novel potential opportunities for their use in bioinks, by comparing latest published studies using algae for 3D bioprinting.
Publisher: MDPI AG
Date: 08-04-2021
DOI: 10.20944/PREPRINTS202104.0240.V1
Abstract: Preecl sia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation that is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to variability and unpredictability of disease manifestation when studied in animal models. After preecl sia, both mothers and offspring have a higher risk of cardiovascular disease (CVD) including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion, however, that therapeutic approach leads to ischemic/reperfusion injury (IRI) often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preecl sia, IRI and HF. Future studies aiming at evaluating CVD in preecl sia patients could benefit from novel models that better mimic the complex scenario described in this article.
Publisher: MDPI AG
Date: 14-06-2023
DOI: 10.3390/DIAGNOSTICS13122057
Abstract: Gastroesophageal reflux disease has a high incidence and prevalence in the general population. Clinical manifestations are heterogenous, and so is the response to medical treatment. Proton pump inhibitors are still the most common agents used to control reflux symptoms and for healing esophagitis, but they are not a one-size-fits-all solution for the disease. Patients with persistent troublesome symptoms despite medical therapy, those experiencing some adverse drug reaction, or those unwilling to take lifelong medications deserve valid alternatives. Anti-reflux Nissen fundoplication is an effective option, but the risk of adverse events has limited its spread. In recent years, advancements in therapeutic endoscopy have been made, and three major endoluminal alternatives are now available, including (1) the delivery of radiofrequency energy to the esophago–gastric junction, (2) transoral incisionless fundoplication (TIF), and (3) anti-reflux mucosal interventions (ARMI) based on mucosal resection (ARMS) and mucosal ablation (ARMA) techniques to remodel the cardia. Endoscopic techniques have shown interesting results, but their diffusion is still limited to expert endoscopists in tertiary centers. This review discusses the state of the art in the endoscopic approach to gastroesophageal reflux disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-03-2014
Abstract: Glutathionylation of endothelial nitric oxide synthase ( eNOS ) “uncouples” the enzyme, switching its function from nitric oxide (NO) to O 2 •− generation. We examined whether this reversible redox modification plays a role in angiotensin II (Ang II)‐induced endothelial dysfunction. Ang II increased eNOS glutathionylation in cultured human umbilical vein endothelial cells (HUVECs), rabbit aorta, and human arteries in vitro. This was associated with decreased NO bioavailability and eNOS activity as well as increased O 2 •− generation. Ang II‐induced decrease in eNOS activity was mediated by glutathionylation, as shown by restoration of function by glutaredoxin‐1. Moreover, Ang II‐induced increase in O 2 •− and decrease in NO were abolished in HUVECs transiently transfected, with mutant eNOS rendered resistant to glutathionylation. Ang II effects were nicotinamide adenine dinucleotide phosphate (NADPH) oxidase dependent because preincubation with gp 91ds‐tat, an inhibitor of NADPH oxidase, abolished the increase in eNOS glutathionylation and loss of eNOS activity. Functional significance of glutathionylation in intact vessels was supported by Ang II‐induced impairment of endothelium‐dependent vasorelaxation that was abolished by the disulfide reducing agent, dithiothreitol. Furthermore, attenuation of Ang II signaling in vivo by administration of an angiotensin converting enzyme (ACE) inhibitor reduced eNOS glutathionylation, increased NO, diminished O 2 •− , improved endothelium‐dependent vasorelaxation and reduced blood pressure. Uncoupling of eNOS by glutathionylation is a key mediator of Ang II‐induced endothelial dysfunction, and its reversal is a mechanism for cardiovascular protection by ACE inhibition. We suggest that Ang II‐induced O 2 •− generation in endothelial cells, although dependent on NADPH oxidase, is lified by glutathionylation‐dependent eNOS uncoupling.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-07-2015
DOI: 10.1161/RES.117.SUPPL_1.310
Abstract: Our previous studies in early mouse embryonic development (E8.2) showing that vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) are expressed in embryonic endothelial cells, but not in embryonic cardiomyocytes, together with the findings by others indicating that NO is required for cardiomyocyte proliferation in mice, led us to investigate the relevancy of the VEGF/eNOS signaling pathway during cardiovascular development. First, wild type and NOS3 knockout mouse embryos between E8.0 and E17.0 were stained with antibodies against smooth muscle α-actin, phospho-histone H3 (PH3), VEGFR2 and PECAM, markers of cardiomyocytes, proliferating, progenitor and endothelial cells, respectively. Our confocal analysis showed hearts of E8.0 NOS3 nulls develop normally. However, E8.5 and E9.5 NOS3 nulls have reduced cardiomyocyte proliferation and impaired heart development. As consequence, hearts of E17 NOS3 nulls were approximately 20% smaller compared to wildtype hearts. To translate our findings to humans, we stained human heart specimens with antibodies against VEGFR2, eNOS, PH3 and sarcomeric α-actinin. Confocal analyses showed for the first time that VEGFR2 is highly expressed in the perinuclear region of human cardiomyocytes of a young donor. They also showed a correlation between eNOS expression and cardiomyocyte proliferation in humans. Consequently, we developed an in vitro three-dimensional co-culture model of human endothelial cells, cardiomyocytes and fibroblasts: “human cardiac tissue spheroids” (HCTSs). Our data showed that laminin and collagen type IV synthesis is increased in VEGF-treated HCTSs generated using CMs from an older donor compared to untreated cultures, suggesting a role for VEGF and eNOS in postnatal human heart development. In conclusion, our data showed that VEGF and eNOS play a similar role in mediating cardiomyocytes proliferation and heart regeneration in both mice and humans. Current studies are focusing on evaluating molecular targets of the VEGF/eNOS signalling pathway in human proliferating cardiomyocytes, which may have significant therapeutical impact for stem cell differentiation, and prevention of cardiovascular complications such as myocardial infarction.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2020
DOI: 10.1007/S43152-020-00026-5
Abstract: 3D bioprinting of cardiovascular tissues for in vitro and in vivo applications is currently investigated as a potential solution to better mimic the microenvironment typical of the human heart. However, optimal cell viability and tissue vascularization remain two of the main challenges in this regard. Silk fibroin (SF) as a natural biomaterial with unique features supports cell survival and tissue vascularization. This review aims to evaluate the potential of hydrogels containing SF in 3D bioprinting of cardiac tissue that better recapitulate the native cardiac microenvironment. SF hydrogels spontaneously develop nanocrystals, which limit their use for 3D bioprinting applications. Nevertheless, the printability of SF is improved in hybrid hydrogels by mixing it with other natural polymers (such as alginate and gelatin). This is achieved by adding SF with other polymers or by crosslinking it by peroxidase catalysis (i.e., with alginate). Compared to only SF-based hydrogels, hybrid hydrogels provide a durable bioprinted construct with improved mechanical stability and biological properties. To date, studies using cardiac cells in bioprinted SF constructs are yet to be performed. Mixing SF with other polymers in bioprinted hybrid hydrogels improves the printability and durability of 3D bioprinted tissues. Studies using these hydrogels with cardiac cells will be required to evaluate the biocompatibility of SF hybrid hydrogels and to establish their potential use for cardiovascular applications.
Publisher: American Chemical Society (ACS)
Date: 07-12-2017
Abstract: Functionalized poly(ethylene dioxythiophene) (f-PEDOT) was copolymerized with two vinyl monomers of different hydrophilicity, acrylic acid and hydroxyethyl methacrylate, to produce electroconductive hydrogels with a range of physical and electronic properties. These hydrogels not only possessed tailored physical properties, such as swelling ratios and mechanical properties, but also displayed electroactivity dependent on the chemical composition of the network. Raman spectroscopy indicated that the functional PEDOT in the hydrogels is in an oxidized form, most likely accounting for the good electrochemical response of the hydrogels observed in physiological buffer. In vitro cell studies showed that cardiac cells respond differently when seeded on hydrogel substrates with different compositions. This study presents a facile approach for the fabrication of electroconductive hydrogels with a range of properties, paving the way for scaffolds that can meet the requirements of different electroresponsive tissues.
Publisher: Frontiers Media SA
Date: 06-10-2021
Publisher: Frontiers Media SA
Date: 18-01-2022
DOI: 10.3389/FROBT.2021.714356
Abstract: Background: Damaged cardiac tissues could potentially be regenerated by transplanting bioengineered cardiac patches to the heart surface. To be fully paradigm-shifting, such patches may need to be transplanted using minimally invasive robotic cardiac surgery (not only traditional open surgery). Here, we present novel robotic designs, initial prototyping and a new surgical operation for instruments to transplant patches via robotic minimally invasive heart surgery. Methods: Robotic surgical instruments and automated control systems were designed, tested with simulation software and prototyped. Surgical proof-of-concept testing was performed on a pig cadaver. Results: Three robotic instrument designs were developed. The first (called “Claw” for the claw-like patch holder at the tip) operates on a rack and pinion mechanism. The second design (“Shell-Beak”) uses adjustable folding plates and rods with a bevel gear mechanism. The third (“HeartSt ”) utilizes a st platform protruding through an adjustable ring. For the HeartSt , rods run through a cylindrical structure designed to fit a uniportal Video-Assisted Thorascopic Surgery (VATS) surgical port. Designed to work with or without a sterile sheath, the patch is pushed out by the st platform as it protrudes. Two instrument robotic control systems were designed, simulated in silico and one of these underwent early ‘sizing and learning’ prototyping as a proof-of-concept. To reflect real surgical conditions, surgery was run “live” and reported exactly (as-it-happened). We successfully picked up, transferred and released a patch onto the heart using the HeartSt in a pig cadaver model. Conclusion: These world-first designs, early prototypes and a novel surgical operation pave the way for robotic instruments for automated keyhole patch transplantation to the heart. Our novel approach is presented for others to build upon free from restrictions or cost—potentially a significant moment in myocardial regeneration surgery which may open a therapeutic avenue for patients unfit for traditional open surgery.
Publisher: Springer Singapore
Date: 2019
Publisher: Elsevier
Date: 2019
Publisher: Elsevier BV
Date: 03-2021
Publisher: Frontiers Media SA
Date: 29-10-2021
DOI: 10.3389/FCELL.2021.750775
Abstract: In recent years, there has been an increasing interest in space exploration, supported by the accelerated technological advancements in the field. This has led to a new potential environment that humans could be exposed to in the very near future, and therefore an increasing request to evaluate the impact this may have on our body, including health risks associated with this endeavor. A critical component in regulating the human pathophysiology is represented by the cardiovascular system, which may be heavily affected in these extreme environments of microgravity and radiation. This mini review aims to identify the impact of microgravity and radiation on the cardiovascular system. Being able to understand the effect that comes with deep space explorations, including that of microgravity and space radiation, may also allow us to get a deeper understanding of the heart and ultimately our own basic physiological processes. This information may unlock new factors to consider with space exploration whilst simultaneously increasing our knowledge of the cardiovascular system and potentially associated diseases.
Publisher: Elsevier BV
Date: 11-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-10-2015
Abstract: Tumor necrosis factor–related apoptosis‐inducing ligand ( TRAIL ) has the ability to inhibit angiogenesis by inducing endothelial cell death, as well as being able to promote pro‐angiogenic activity in vitro. These seemingly opposite effects make its role in ischemic disease unclear. Using Trail −/− and wildtype mice, we sought to determine the role of TRAIL in angiogenesis and neovascularization following hindlimb ischemia. Reduced vascularization assessed by real‐time 3‐dimensional Vevo ultrasound imaging and CD 31 staining was evident in Trail −/− mice after ischemia, and associated with reduced capillary formation and increased apoptosis. Notably, adenoviral TRAIL administration significantly improved limb perfusion, capillary density, and vascular smooth‐muscle cell content in both Trail −/− and wildtype mice. Fibroblast growth factor‐2, a potent angiogenic factor, increased TRAIL expression in human microvascular endothelial cell‐1, with fibroblast growth factor‐2‐mediated proliferation, migration, and tubule formation inhibited with TRAIL si RNA . Both fibroblast growth factor‐2 and TRAIL significantly increased NADPH oxidase 4 ( NOX 4) expression. TRAIL ‐inducible angiogenic activity in vitro was inhibited with si RNA s targeting NOX 4, and consistent with this, NOX 4 mRNA was reduced in 3‐day ischemic hindlimbs of Trail −/− mice. Furthermore, TRAIL ‐induced proliferation, migration, and tubule formation was blocked by scavenging H 2 O 2 , or by inhibiting nitric oxide synthase activity. Importantly, TRAIL ‐inducible endothelial nitric oxide synthase phosphorylation at Ser‐1177 and intracellular human microvascular endothelial cell‐1 cell nitric oxide levels were NOX 4 dependent. This is the first report demonstrating that TRAIL can promote angiogenesis following hindlimb ischemia in vivo. The angiogenic effect of TRAIL on human microvascular endothelial cell‐1 cells is downstream of fibroblast growth factor‐2, involving NOX 4 and nitric oxide signaling. These data have significant therapeutic implications, such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with cardiovascular disease and diabetes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2021
DOI: 10.1161/HYPERTENSIONAHA.120.16884
Abstract: Nitric oxide (NO) production by eNOS (endothelial NO synthase) is critical for vascular health. Oxidative stress-induced uncoupling of eNOS leads to decreased NO bioavailability, compounded by increased superoxide generation. FXYD1 (FXYD domain containing ion transport regulator 1), a caveolar protein, protects against oxidative inhibition of the Na + -K + -ATPase. We hypothesized that FXYD1 may afford a similar inhibition of oxidative dysregulation of eNOS, providing a broader protection within caveolae. FXYD1-eNOS colocalization was demonstrated by co-immunoprecipitation in heart protein and by proximity ligation assay in human umbilical vein endothelial cells. The functional nature of this partnership was shown by silencing FXYD1 in human umbilical vein endothelial cells, where 50% decreased NO and 2-fold augmented superoxide was shown. Three-dimensional cocultured cardiac spheroids generated from FXYD1 knockout mice were incapable of acetylcholine-induced NO production. Overexpression of FXYD1 in HEK293 cells revealed a possible mechanism, where FXYD1 protected against redox modification of eNOS cysteines. In vivo, vasodilation in response to increasing doses of bradykinin was impaired in knockout mice, and this was rescued in mice by delivery of FXYD1 protein packaged in exosomes. Bloods vessels extracted from knockout mice exhibited increased oxidative and nitrosative stress with evidence of reduce eNOS phosphorylation. Impaired vascular function and augmented superoxide generation were also evident in diabetic knockout mice. Despite this, blood pressure was similar in wildtype and knockout mice, but after chronic angiotensin II infusion, knockout of FXYD1 was associated with a heightened blood pressure response. FXYD1 protects eNOS from dysregulated redox signaling and is protective against both hypertension and diabetic vascular oxidative stress.
Publisher: Elsevier BV
Date: 03-2022
Publisher: Springer Science and Business Media LLC
Date: 08-2017
DOI: 10.1038/S41598-017-06385-8
Abstract: Three-dimensional in vitro cell systems are a promising alternative to animals to study cardiac biology and disease. We have generated three-dimensional in vitro models of the human heart (“cardiac spheroids”, CSs) by co-culturing human primary or iPSC-derived cardiomyocytes, endothelial cells and fibroblasts at ratios approximating those present in vivo . The cellular organisation, extracellular matrix and microvascular network mimic human heart tissue. These spheroids have been employed to investigate the dose-limiting cardiotoxicity of the common anti-cancer drug doxorubicin. Viability/cytotoxicity assays indicate dose-dependent cytotoxic effects, which are inhibited by the nitric oxide synthase (NOS) inhibitor L-NIO, and genetic inhibition of endothelial NOS, implicating peroxynitrous acid as a key damaging agent. These data indicate that CSs mimic important features of human heart morphology, biochemistry and pharmacology in vitro , offering a promising alternative to animals and standard cell cultures with regard to mechanistic insights and prediction of toxic effects in human heart tissue.
Publisher: Wiley
Date: 25-11-2008
DOI: 10.1002/DVDY.21825
Publisher: Informa Healthcare
Date: 04-02-2010
Publisher: MDPI AG
Date: 14-04-2021
Abstract: Preecl sia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation, and is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to the variability and unpredictability of disease manifestation when studied in animal models. After preecl sia, both mothers and offspring have a higher risk of cardiovascular disease (CVD), including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion however, this therapeutic approach leads to ischemic/reperfusion injury (IRI), often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preecl sia, IRI and HF. Future studies aiming at evaluating CVD in preecl sia patients could benefit from novel models that better mimic the complex scenario described in this article.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Wiley
Date: 03-07-2023
DOI: 10.1111/DEN.14606
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2012
DOI: 10.1161/ATVB.32.SUPPL_1.A237
Abstract: To evaluate when nitric oxide (NO) is first expressed in the EC lineage, the expression pattern of eNOS, phosphorylated eNOS (P-eNOS), and key proteins that define the endothelial lineage (i.e., Flk-1, TAL-1, CD31) were assessed in 7.0-8.5dpc mouse embryos. Immunohistochemical analyses revealed that embryonic endothelial cells (Flk-1 + /TAL-1 + / CD31 + ) expressed eNOS prior to their investment by smooth muscle cells while isolated angioblasts (Flk-1 + /TAL-1 + / CD31 - ) did not express eNOS. Based on eNOS expression we identified a cell type, transitional angioblasts ( eNOS + / FLK-1 + /TAL-1 + / CD31 - ), intermediate between embryonic endothelial cells (EECs) and angioblasts. Transitional angioblasts are further distinguished from angioblasts by their initiation of cell-cell contacts with other eNOS + Flk-1 + /TAL-1 + /CD31 - cells or with EECs. Analysis of P-eNOS and phospho-histone H3 expression in transitional angioblasts and EECs showed a tight correlation between P-eNOS expression and cell proliferation. This correlation was also observed in cultured human umbilical vein endothelial cells (HUVECs) treated with nocodazole to induce a G2/M cell cycle block. Given that VEGF mediates both EC ision and NO production, we evaluated whether VEGF-mediated NO production is critical for neovascular processes (vasculogenesis/angiogenesis). We show using allantoic cultures that VEGF-mediated mitosis in Flk-1 + cells is decreased by the eNOS inhibitors L-NIO and 17-AAG, suggesting that VEGF-mediated eNOS phosphorylation is regulating cell proliferation. Supporting such a role, we found that the alterations in VEGF-mediated vascular patterning we observed in response to eNOS inhibitors were consistent with an overall reduction in the EEC numbers and that VEGF-induced NO production in HUVECs increased the S-nitrosylation of proteins important for the regulation of the G2/M transition, such as cyclin B. Taken together, our findings suggest that VEGF-mediated eNOS phosphorylation regulates transitional angioblast, EEC, and EC proliferation.
Publisher: Bentham Science Publishers Ltd.
Date: 10-10-2016
DOI: 10.2174/1574888X10666151001114848
Abstract: Engineering of in vitro three-dimensional cultures of stem cells and their progenies has offered promising alternatives to recapitulate the in vivo microenvironment, or stem cell niche, and has provided more specific cues for proper stem cell differentiation, maintenance and culture. In particular, tissue spheroids are cellular aggregates with defined cellular and extracellular features and have provided optimal conditions for stem cell technology, both in culture and for potential engraftment. Recent studies have focused on spheroid formation and the developmental roles played by cellular and extracellular signals necessary for cellular aggegation into spheroids. This review will provide insights into the factors that regulate in vitro spheroid formation by comparing them with their developmental counterparts in vivo. At the same time, we will identify cellular and extracellular signals that could be used to bioengineer spheroids with improved features according to their application. Finally, this review will provide an overview of the applications to date of spheroid cultures of stem cells and their progenies, providing insights for future studies.
Location: Belgium
Location: United States of America
Start Date: 2021
End Date: 2021
Funder: Australian Research Council
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: University of Sydney
View Funded ActivityStart Date: 2011
End Date: 2013
Funder: American Heart Association
View Funded ActivityStart Date: 2017
End Date: 2017
Funder: University of Sydney
View Funded ActivityStart Date: 2017
End Date: 2018
Funder: University of Sydney
View Funded ActivityStart Date: 2021
End Date: 12-2021
Amount: $289,500.00
Funder: Australian Research Council
View Funded Activity