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Find video protocols related to scientific articles indexed in Pubmed.
Elimination of Remaining Undifferentiated Induced Pluripotent Stem Cells in the Process of Human Cardiac Cell Sheet Fabrication Using a Methionine-Free Culture Condition.
Tissue Eng Part C Methods
PUBLISHED: 09-24-2014
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Cardiac tissue engineering is a promising method for regenerative medicine. Although we have developed human cardiac cell sheets by integration of cell sheet-based tissue engineering and scalable bioreactor culture, the risk of contamination by induced pluripotent stem (iPS) cells in cardiac cell sheets remains unresolved. In the present study, we established a novel culture method to fabricate human cardiac cell sheets with a decreased risk of iPS cell contamination while maintaining viabilities of iPS cell-derived cells, including cardiomyocytes and fibroblasts, using a methionine-free culture condition. When cultured in the methionine-free condition, human iPS cells did not survive without feeder cells and could not proliferate or form colonies on feeder cells or in coculture with cells for cardiac cell sheet fabrication. When iPS cell-derived cells after the cardiac differentiation were transiently cultured in the methionine-free condition, gene expression of OCT3/4 and NANOG was downregulated significantly compared with that in the standard culture condition. Furthermore, in fabricated cardiac cell sheets, spontaneous and synchronous beating was observed in the whole area while maintaining or upregulating the expression of various cardiac and extracellular matrix genes. These findings suggest that human iPS cells are methionine dependent and a methionine-free culture condition for cardiac cell sheet fabrication might reduce the risk of iPS cell contamination.
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Oxygen consumption of human heart cells in monolayer culture.
Biochem. Biophys. Res. Commun.
PUBLISHED: 08-27-2014
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Tissue engineering in cardiovascular regenerative therapy requires the development of an efficient oxygen supply system for cell cultures. However, there are few studies which have examined human cardiomyocytes in terms of oxygen consumption and metabolism in culture. We developed an oxygen measurement system equipped with an oxygen microelectrode sensor and estimated the oxygen consumption rates (OCRs) by using the oxygen concentration profiles in culture medium. The heart is largely made up of cardiomyocytes, cardiac fibroblasts, and cardiac endothelial cells. Therefore, we measured the oxygen consumption of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), cardiac fibroblasts, human cardiac microvascular endothelial cell and aortic smooth muscle cells. Then we made correlations with their metabolisms. In hiPSC-CMs, the value of the OCR was 0.71±0.38pmol/h/cell, whereas the glucose consumption rate and lactate production rate were 0.77±0.32pmol/h/cell and 1.61±0.70pmol/h/cell, respectively. These values differed significantly from those of the other cells in human heart. The metabolism of the cells that constitute human heart showed the molar ratio of lactate production to glucose consumption (L/G ratio) that ranged between 1.97 and 2.2. Although the energy metabolism in adult heart in vivo is reported to be aerobic, our data demonstrated a dominance of anaerobic glycolysis in an in vitro environment. With our measuring system, we clearly showed the differences in the metabolism of cells between in vivo and in vitro monolayer culture. Our results regarding cell OCRs and metabolism may be useful for future tissue engineering of human heart.
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Cell sheet technology for cardiac tissue engineering.
Methods Mol. Biol.
PUBLISHED: 07-30-2014
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In this chapter, we describe the methods for the fabrication and transfer/transplantation of 3D tissues by using cell sheet technology for cardiac tissue regeneration. A temperature-responsive culture surface can be fabricated by grafting a temperature-responsive polymer, poly(N-isopropylacrylamide), onto a polystyrene cell culture surface. Cells cultured confluently on such a culture surface can be recovered as an intact cell sheet, and functional three-dimensional (3D) tissues can then be easily fabricated by layering the recovered cell sheets without any scaffolds or complicated manipulation. Cardiac cell sheets, myoblast sheets, mesenchymal stem cell sheets, cardiac progenitor cell sheets, etc., which are prepared from temperature-responsive culture surfaces, can be easily transplanted onto heart tissues of animal models, and those cell sheet constructs enhance the cell transplant efficiency, resulting in the induction of effective therapy.
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Cell sheet approach for tissue engineering and regenerative medicine.
J Control Release
PUBLISHED: 02-25-2014
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After the biotech medicine era, regenerative medicine is expected to be an advanced medicine that is capable of curing patients with difficult-to-treat diseases and physically impaired function. Our original scaffold-free cell sheet-based tissue engineering technology enables transplanted cells to be engrafted for a long time, while fully maintaining their viability. This technology has already been applied to various diseases in the clinical setting, including the cornea, esophagus, heart, periodontal ligament, and cartilage using autologous cells. Transplanted cell sheets not only replace the injured tissue and compensate for impaired function, but also deliver growth factors and cytokines in a spatiotemporal manner over a prolonged period, which leads to promotion of tissue repair. Moreover, the integration of stem cell biology and cell sheet technology with sufficient vascularization opens possibilities for fabrication of human three-dimensional vascularized dense and intact tissue grafts for regenerative medicine to parenchymal organs.
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Toward the development of bioengineered human three-dimensional vascularized cardiac tissue using cell sheet technology.
Int Heart J
PUBLISHED: 01-27-2014
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Bioengineered cardiac tissue is expected to be applied to regenerative medicine and tissue models for disease research and drug screening. Recent and rapid progress in technologies for tissue engineering approaches, including cell sheet technology, vascularization of thickened tissues, and large-scale expansion and differentiation of pluripotent stem cells, is about to realize the fabrication of human three-dimensional cardiac tissue. However, a remaining challenge is to make these fabricated tissues closely resemble the phenotypes, and to perform the functions of human cardiac tissue.
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Hydrophobized thermoresponsive copolymer brushes for cell separation by multistep temperature change.
Biomacromolecules
PUBLISHED: 09-25-2013
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For preparing a thermally modulated biointerface that separates cells without the modification of cell surfaces for regenerative medicine and tissue engineering, poly(N-isopropylacrylamide-co-butyl methacrylate) (P(IPAAm-co-BMA), thermo-responsive hydrophobic copolymer brushes with various BMA composition were formed on glass substrate through a surface-initiated atom transfer radical polymerization (ATRP). Characterization of the prepared surface was performed by X-ray photoelectron spectroscopy (XPS), attenuated total reflection Fourier transform infrared spectroscopy (ATR/FT-IR), and gel-permeation chromatography (GPC) measurement. Prepared copolymer brush surfaces were characterized by observing the adhesion (37 °C) and detachment (20 or 10 °C) of four types of human cells: human umbilical vein endothelial cells (HUVECs), normal human dermal fibroblasts (NHDFs), human aortic smooth muscle cells (SMCs), and human skeletal muscle myoblast cells (HSMMs). HUVECs and NHDFs exhibited their effective detachment temperature at 20 and 10 °C, respectively. Using cells intrinsic temperature sensitivity for detachment from the copolymer brush, a mixture of green fluorescent protein (GFP)-expressing HUVECs (GFP-HUVECs) and NHDFs was separated.
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Cell sheet-based cardiac tissue engineering.
Anat Rec (Hoboken)
PUBLISHED: 09-13-2013
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Tissue engineering is indispensable for the advancement of regenerative medicine and the development of tissue models. Cell sheet-based method is one the promising strategies for cardiac tissue engineering. To date, cell sheet transplantation using wide variety of cells has been performed for the treatment of various heart diseases. These cell sheet transplantations have shown to ameliorate cardiac dysfunction and improve symptoms of heart failure. Recent progress of the technologies on the layering of cardiac cell sheets accompanied with vascularization and the large scale cultivation system of embryonic stem cell and induced pluripotent stem cell is about to turn the fabrication of thickened human cardiac tissue for transplant and tissue models into reality. Anat Rec, 297:65-72. 2014. © 2013 Wiley Periodicals, Inc.
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Cardiac side population cells and Sca-1-positive cells.
Methods Mol. Biol.
PUBLISHED: 06-29-2013
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Since the resident cardiac stem/progenitor cells were discovered, their ability to maintain the architecture and functional integrity of adult heart has been broadly explored. The methods for isolation and purification of the cardiac stem cells are crucial for the precise analysis of their developmental origin and intrinsic potential as tissue stem cells. Stem cell antigen-1 (Sca-1) is one of the useful cell surface markers to purify the cardiac progenitor cells. Another purification strategy is based on the high efflux ability of the dye, which is a common feature of tissue stem cells. These dye-extruding cells have been called side population cells because they locate in the side of dye-retaining cells after fluorescent cell sorting. In this chapter, we describe the methodology for the isolation of cardiac SP cells and Sca-1 positive cells.
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Simple suspension culture system of human iPS cells maintaining their pluripotency for cardiac cell sheet engineering.
J Tissue Eng Regen Med
PUBLISHED: 03-19-2013
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In this study, a simple three-dimensional (3D) suspension culture method for the expansion and cardiac differentiation of human induced pluripotent stem cells (hiPSCs) is reported. The culture methods were easily adapted from two-dimensional (2D) to 3D culture without any additional manipulations. When hiPSCs were directly applied to 3D culture from 2D in a single-cell suspension, only a few aggregated cells were observed. However, after 3?days, culture of the small hiPSC aggregates in a spinner flask at the optimal agitation rate created aggregates which were capable of cell passages from the single-cell suspension. Cell numbers increased to approximately 10-fold after 12?days of culture. The undifferentiated state of expanded hiPSCs was confirmed by flow cytometry, immunocytochemistry and quantitative RT-PCR, and the hiPSCs differentiated into three germ layers. When the hiPSCs were subsequently cultured in a flask using cardiac differentiation medium, expression of cardiac cell-specific genes and beating cardiomyocytes were observed. Furthermore, the culture of hiPSCs on Matrigel-coated dishes with serum-free medium containing activin A, BMP4 and FGF-2 enabled it to generate robust spontaneous beating cardiomyocytes and these cells expressed several cardiac cell-related genes, including HCN4, MLC-2a and MLC-2v. This suggests that the expanded hiPSCs might maintain the potential to differentiate into several types of cardiomyocytes, including pacemakers. Moreover, when cardiac cell sheets were fabricated using differentiated cardiomyocytes, they beat spontaneously and synchronously, indicating electrically communicative tissue. This simple culture system might enable the generation of sufficient amounts of beating cardiomyocytes for use in cardiac regenerative medicine and tissue engineering. Copyright © 2013 John Wiley & Sons, Ltd.
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Cell sheet transplantation for heart tissue repair.
J Control Release
PUBLISHED: 02-24-2013
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Cell transplantation is attracting considerable attention as the next-generation therapy for treatment of cardiovascular diseases. We have developed cell sheet engineering as a type of scaffold-less tissue engineering for application in myocardial tissue engineering and the repair of injured heart tissue by cell transplantation. Various types of cell sheet transplantation have improved cardiac function in animal models and clinical settings. Furthermore, cell-based tissue engineering with human induced pluripotent stem cell technology is about to create thick vascularized cardiac tissue for cardiac grafts and heart tissue models. In this review, we summarize the current cardiac cell therapies for treating heart failure with cell sheet technology and cell sheet-based tissue engineering.
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Cardiac cell sheet transplantation improves damaged heart function via superior cell survival in comparison with dissociated cell injection.
Tissue Eng Part A
PUBLISHED: 08-29-2011
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Regenerative therapies have currently emerged as one of the most promising treatments for repair of the damaged heart. Recently, numerous researchers reported that isolated cell injection treatments can improve heart function in myocardial infarction models. However, significant cell loss due to primary hypoxia or cell wash-out and difficulty to control the location of the grafted cells remains problem. As an attempt to overcome these limitations, we have proposed cell sheet-based tissue engineering, which involves stacking confluently cultured cells (two-dimensional), cell sheets, to construct three-dimensional cell-dense tissues. Cell sheet transplantation has been able to recover damaged heart function. However, no detailed analysis for transplanted cell survival has been previously performed. The present study compared the survival of cardiac cell sheet transplantation to direct cell injection in a rat myocardial infarction model. Luciferase-expressing neonatal rat cardiac cells were harvested as cell sheets from temperature-responsive culture dishes. The transplantation of cell sheets was compared to the direct injection of isolated cells dissociated with trypsin-ethylenediaminetetraacetic acid. These grafts were transplanted to infarcted rat hearts and cardiac function was assessed by echocardiography at 2 and 4 weeks after transplantation. In vivo bioluminescence and histological analyses were performed to examine cell survival. Cell sheet transplantation consistently yielded greater cell survival than cell injection. Immunohistochemistry revealed that cardiac cell sheets existed over the infarcted area as an intact layer. In contrast, the injected cells were scattered with relatively few cardiomyocytes in the infarcted areas. Four weeks after transplantation, cardiac function was also significantly improved in the cell sheet transplantation group compared with the cell injection. Twenty-four hours after cell grafting, significantly greater numbers of mature capillaries were also observed in the cardiac cell sheet transplantation. Additionally, the numbers of apoptotic cells with deterioration of integrin-mediated attachment were significantly lower after cardiac cell sheet transplantation. In accordance with increased cell survival, cardiac function was significantly improved after cardiac cell sheet transplantation in comparison to cell injection. Cell sheet transplantation can repair damaged hearts through improved cell survival and should become a promising therapy in cardiovascular regenerative medicine.
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A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure.
PLoS ONE
PUBLISHED: 08-21-2011
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Infusion of bone marrow-derived mononuclear cells (BMMNC) has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM) without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH) secreted from myeloid (Gr-1(+)) cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+) cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+) cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+) cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC) via activation of NF?B. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure.
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The pleiotropic effects of ARB in vascular endothelial progenitor cells.
Curr Vasc Pharmacol
PUBLISHED: 05-21-2011
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Angiotensin II regulates blood pressure and contributes to endothelial dysfunction and the progression of atherosclerosis. Bone marrow-derived endothelial progenitor cells (EPCs) in peripheral blood contribute to postnatal vessel repair and neovascularization. Impaired EPC function in patients with hypertension and diabetes inhibits the endogenous repair of vascular lesions and leads to the progression of atherosclerosis. The number of EPCs in peripheral blood is inversely correlated with mortality and the occurrence of cardiovascular events. Angiotensin II-mediated signaling is implicated in oxidative stress, inflammation and insulin resistance, factors that cause EPC dysfunction. Blockade of the angiotensin II type 1 receptor may therefore present a new therapeutic target for enhancing EPC function.
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Creation of mouse embryonic stem cell-derived cardiac cell sheets.
Biomaterials
PUBLISHED: 05-02-2011
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Research on heart tissue engineering is an exciting and promising area. Although we previously developed bioengineered myocardium using cell sheet-based tissue engineering technologies, the issue of appropriate cell sources remained unresolved. In the present study, we created cell sheets of mouse embryonic stem (ES) cell-derived cardiomyocytes after expansion in three-dimensional stirred suspension cultures. Serial treatment of the suspension cultures with noggin and granulocyte colony-stimulating factor significantly increased the number of cardiomyocytes by more than fourfold compared with untreated cultures. After drug selection for ES cells expressing the neomycin-resistance gene under the control of the ?-myosin heavy chain promoter, almost all of the cells showed spontaneous beating and expressed several cardiac contractive proteins in a fine striated pattern. When ES-derived cardiomyocytes alone were seeded onto temperature-responsive culture dishes, cell sheets were not created, whereas cocultures with cardiac fibroblasts promoted cell sheet formation. The cardiomyocytes in the cell sheets beat spontaneously and synchronously, and expressed connexin 43 at the edge of adjacent cardiomyocytes. Furthermore, when the extracellular action potential was recorded, unidirectional action potential propagation was observed. The present findings suggest that stirred suspension cultures with appropriate growth factors are capable of producing cardiomyocytes effectively and easily, and that ES-derived cardiac cell sheets may be a promising tool for the development of bioengineered myocardium.
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Implantation of cardiac progenitor cells using self-assembling peptide improves cardiac function after myocardial infarction.
J. Mol. Cell. Cardiol.
PUBLISHED: 02-18-2010
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Implantation of various types of cells into the heart has been reported to be effective for heart failure, however, it is unknown what kinds of cells are most suitable for myocardial repair. To examine which types of cells are most effective, we injected cell-Puramatrix™ (PM) complex into the border area and overlaid the cell-PM patch on the myocardial infarction (MI) area. We compared cardiac morphology and function at 2 weeks after transplantation. Among clonal stem cell antigen-1 positive cardiac progenitors with PM (cSca-1/PM), bone marrow mononuclear cells with PM (BM/PM), skeletal myoblasts with PM (SM/PM), adipose tissue-derived mesenchymal cells with PM (AMC/PM), PM alone (PM), and non-treated MI group (MI), the infarct area of cSca-1/PM was smaller than that of BM/PM, SM/PM, PM and MI. cSca-1/PM and AMC/PM attenuated ventricular enlargement and restored cardiac function in comparison with MI. Capillary density in the infarct area of cSca-1/PM was higher than that of other five groups. The percentage of TUNEL positive cardiomyocytes in the infarct area of cSca-1/PM was lower than that of MI and PM. cSca-1 secreted VEGF and some of them differentiated into cardiomyocytes and vascular smooth muscle cells. These results suggest that transplantation of cSca-1/PM most effectively prevents cardiac remodeling and dysfunction through angiogenesis, inhibition of apoptosis and myocardial regeneration.
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Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice.
J. Clin. Invest.
PUBLISHED: 05-27-2009
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Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1-positive (Sca-1-positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.
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Telmisartan induces proliferation of human endothelial progenitor cells via PPARgamma-dependent PI3K/Akt pathway.
Atherosclerosis
PUBLISHED: 02-06-2009
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Although recent clinical trials have suggested that angiotensin II type 1 receptor blockers (ARBs) reduced cardiovascular events, the precise mechanisms involved are still unknown. Telmisartan, an ARB, has recently been identified as a ligand of peroxisome proliferator-activated receptor-gamma (PPARgamma). On the other hand, since endothelial progenitor cells (EPCs) are thought to play a critical role in ischemic diseases, we investigated effects of telmisartan on proliferation of EPCs.
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Fabrication of mouse embryonic stem cell-derived layered cardiac cell sheets using a bioreactor culture system.
PLoS ONE
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Bioengineered functional cardiac tissue is expected to contribute to the repair of injured heart tissue. We previously developed cardiac cell sheets using mouse embryonic stem (mES) cell-derived cardiomyocytes, a system to generate an appropriate number of cardiomyocytes derived from ES cells and the underlying mechanisms remain elusive. In the present study, we established a cultivation system with suitable conditions for expansion and cardiac differentiation of mES cells by embryoid body formation using a three-dimensional bioreactor. Daily conventional medium exchanges failed to prevent lactate accumulation and pH decreases in the medium, which led to insufficient cell expansion and cardiac differentiation. Conversely, a continuous perfusion system maintained the lactate concentration and pH stability as well as increased the cell number by up to 300-fold of the seeding cell number and promoted cardiac differentiation after 10 days of differentiation. After a further 8 days of cultivation together with a purification step, around 1 × 10(8) cardiomyocytes were collected in a 1-L bioreactor culture, and additional treatment with noggin and granulocyte colony stimulating factor increased the number of cardiomyocytes to around 5.5 × 10(8). Co-culture of mES cell-derived cardiomyocytes with an appropriate number of primary cultured fibroblasts on temperature-responsive culture dishes enabled the formation of cardiac cell sheets and created layered-dense cardiac tissue. These findings suggest that this bioreactor system with appropriate medium might be capable of preparing cardiomyocytes for cell sheet-based cardiac tissue.
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Creation of human cardiac cell sheets using pluripotent stem cells.
Biochem. Biophys. Res. Commun.
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Although we previously reported the development of cell-dense thickened cardiac tissue by repeated transplantation-based vascularization of neonatal rat cardiac cell sheets, the cell sources for human cardiac cells sheets and their functions have not been fully elucidated. In this study, we developed a bioreactor to expand and induce cardiac differentiation of human induced pluripotent stem cells (hiPSCs). Bioreactor culture for 14 days produced around 8×10(7) cells/100 ml vessel and about 80% of cells were positive for cardiac troponin T. After cardiac differentiation, cardiomyocytes were cultured on temperature-responsive culture dishes and showed spontaneous and synchronous beating, even after cell sheets were detached from culture dishes. Furthermore, extracellular action potential propagation was observed between cell sheets when two cardiac cell sheets were partially overlaid. These findings suggest that cardiac cell sheets formed by hiPSC-derived cardiomyocytes might have sufficient properties for the creation of thickened cardiac tissue.
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