Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes

Kehat, Izhak; Kenyagin-Karsenti, Dorit; Snir, Mirit; Segev, Hana; Amit, Michal; Gepstein, Amira; Livne, Erella; Binah, Ofer; Itskovitz‐Eldor, Joseph; Gepstein, Lior

doi:10.1172/jci12131

Cited by 859 publications

(852 citation statements)

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“…EBs at differentiated day 13 are equivalent to embryos at an mid-early developmental stage. Cardiomyocytes at this stage are electrophysiologically immature [14,15], and Cx43 is distributed scattered inside the cell and in the cell membrane. Our findings suggest that the Cx43 distribution tends to be more mature in the CO group, but whether cocultivation improves the maturity of differentiated cardiomyocytes still needs to be further studied.…”

Section: Discussionmentioning

confidence: 99%

“…In the mouse, Cx43 is expressed at embryonic day12.5 in the trabeculated myocardium but not in the compact tissue and is uniformly expressed across the entire ventricular myocardium by embryonic day 17.5 [13]. Cardiomyocytes derived from human ES cells display structural and functional properties of early-stage cardiomyocytes [14], are electrophysiologically immature and exhibit automaticity [15]. …”

Section: Introductionmentioning

confidence: 99%

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Coculture of Embryonic Ventricular Myocytes and Mouse Embryonic Stem Cell Enhance Intercellular Signaling by Upregulation of Connexin43

Tang

Liang

et al. 2013

Cell Physiol Biochem

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Background: Stem cell therapy has been proposed as a potential treatment strategy for ischemic cardiomyopathy in recent years. A variety of stem cells or stem cell-derived cells can potentially be used for transplantation. Despite improved cardiac function after treatment, one of the major problems is the poor integration between host and donor cells which can lead to post-transplantation arrhythmia and poor long-term outcome. Methods: In the present study, we cocultured murine embryonic stem cells (mES) with murine embryonic ventricular myocytes (mEVs) in hanging drops to assess the cellular interaction and function of mES-derived cardiomyocytes under these conditions. Results: We found that when mEVs are added to a culture system of embryonic stem cells, the number of spontaneously beating areas in embryoid bodies (EBs) increases, intercellular gap junction communication is enhanced by upregulation of Cx43 expression at the mid-developmental stage and Cx43 is distributed more orderly between cardiomyocytes. Conclusions: Our findings suggest mES-derived cardiomyocytes are able to form effective signaling pathways through coculture with mEVs which is important for providing more functional grafts for cardiac cell therapy by improving the integration between transplanted and host cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Coculture of Embryonic Ventricular Myocytes and Mouse Embryonic Stem Cell Enhance Intercellular Signaling by Upregulation of Connexin43

Tang

Liang

et al. 2013

Cell Physiol Biochem

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“…The optimal cell source to create an engineered myocardial patch should be easy to harvest, proliferative, non-immunogenic and has the ability to differentiate into mature, functional cardiomyocytes. Studies have shown that after expansion, stem cells can be directed to differentiate into cardiomyogenic lineages [28,29] . Cardiomyocytes have natural contractile and electrophysiological properties, are difficult to obtain, to expand, and are allogenic.…”

Section: Introductionmentioning

confidence: 99%

Cardiogenic differentiation of mesenchymal stem cells on elastomeric poly (glycerol sebacate)/collagen core/shell fibers

Ravichandran¹

2013

WJC

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AIM:To facilitate engineering of suitable biomaterials to meet the challenges associated with myocardial infarction. METHODS:Poly (glycerol sebacate)/collagen (PGS/ collagen) core/shell fibers were fabricated by core/ shell electrospinning technique, with core as PGS and shell as collagen polymer; and the scaffolds were characterized by scanning electron microscope (SEM), fourier transform infrared spectroscopy (FTIR), contact angle and tensile testing for cardiac tissue engineering. Collagen nanofibers were also fabricated by electrospinning for comparison with core/shell fibers. Studies on cell-scaffold interaction were carried out using cardiac cells and mesenchymal stem cells (MSCs) co-culture system with cardiac cells and MSCs separately serving as positive and negative controls respectively. The co-culture system was characterized for cell proliferation and differentiation of MSCs into cardiomyogenic lineage in the co-culture environment using dual immunocytochemistry. The co-culture cells were stained with cardiac specific marker proteins like actinin and troponin and MSC specific marker protein CD 105 for proving the cardiogenic differentiation of MSCs. Further the morphology of cells was analyzed using SEM.RESULTS: PGS/collagen core/shell fibers, core is PGS polymer having an elastic modulus related to that of cardiac fibers and shell as collagen, providing natural environment for cellular activities like cell adhesion, proliferation and differentiation. SEM micrographs of electrospun fibrous scaffolds revealed porous, beadless, uniform fibers with a fiber diameter in the range of 380 ± 77 nm and 1192 ± 277 nm for collagen fibers and PGS/collagen core/shell fibers respectively. The obtained PGS/collagen core/shell fibrous scaffolds were hydrophilic having a water contact angle of 17.9 ± 4.6° compared to collagen nanofibers which had a contact angle value of 30 ± 3.2°. The PGS/collagen core/shell fibers had mechanical properties comparable to that of native heart muscle with a young's modulus of 4.24 ± 0.7 MPa, while that of collagen nanofibers was comparatively higher around 30.11 ± 1.68 MPa. FTIR spectrum was performed to confirm the functional groups present in the electrospun scaffolds. Amide Ⅰ and amide Ⅱ of collagen were detected at 1638.

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“…H uman pluripotent stem cells, such as embryonic stem cells (ESC) and induced pluripotent stem cells, self-renew; their differentiation to the cardiac lineage [1][2][3][4][5][6] represents a potentially unlimited source of ventricular cardiomyocytes (VCMs) for therapies and as experimental models to investigate mechanisms involved in human cardiac development and disease progression. Successful application of human ESC (hESC)-ventricular cardiomyocytes (VCMs) to myocardial repair or modeling requires that the cells faithfully recapitulate the phenotype of adult CMs, especially in relation to their electrophysiological, contractile, and metabolic functions.…”

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confidence: 99%

Proteomic Analysis of Human Pluripotent Stem Cell–Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation

Poon

Keung

Liang

et al. 2015

Circ Cardiovasc Genet

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Background-Differentiation of pluripotent human embryonic stem cells (hESCs) to the cardiac lineage represents a potentially unlimited source of ventricular cardiomyocytes (VCMs), but hESC-VCMs are developmentally immature. Previous attempts to profile hESC-VCMs primarily relied on transcriptomic approaches, but the global proteome has not been examined. Furthermore, most hESC-CM studies focus on pathways important for cardiac differentiation, rather than regulatory mechanisms for CM maturation. We hypothesized that gene products and pathways crucial for maturation can be identified by comparing the proteomes of hESCs, hESC-derived VCMs, human fetal and human adult ventricular and atrial CMs. Methods and Results-Using two-dimensional-differential-in-gel electrophoresis, 121 differentially expressed (>1.5-fold; P<0.05) proteins were detected. The data set implicated a role of the peroxisome proliferator-activated receptor α signaling in cardiac maturation. Consistently, WY-14643, a peroxisome proliferator-activated receptor α agonist, increased fatty oxidative enzyme level, hyperpolarized mitochondrial membrane potential and induced a more organized morphology. Along this line, treatment with the thyroid hormone triiodothyronine increased the dynamic tension developed in engineered human ventricular cardiac microtissue by 3-fold, signifying their maturation. Conclusions-We conclude that the peroxisome proliferator-activated receptor α and thyroid hormone pathways modulate the metabolism and maturation of hESC-VCMs and their engineered tissue constructs. These results may lead to mechanism-based methods for deriving mature chamber-specific CMs.

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Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes

Cited by 859 publications

References 29 publications

Coculture of Embryonic Ventricular Myocytes and Mouse Embryonic Stem Cell Enhance Intercellular Signaling by Upregulation of Connexin43

Coculture of Embryonic Ventricular Myocytes and Mouse Embryonic Stem Cell Enhance Intercellular Signaling by Upregulation of Connexin43

Cardiogenic differentiation of mesenchymal stem cells on elastomeric poly (glycerol sebacate)/collagen core/shell fibers

Proteomic Analysis of Human Pluripotent Stem Cell–Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation

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