Survival and maturation of human embryonic stem cell-derived cardiomyocytes in rat hearts

Dai, Wangde; Field, Loren J.; Rubart, Michael; Reuter, Sean; Hale, Sharon L.; Zweigerdt, Robert; Graichen, Ralph; Kay, Gregory L.; Jyrälä, Aarne; Colman, Alan; Davidson, Bruce P.; Pera, Martin F.; Kloner, Robert A.

doi:10.1016/j.yjmcc.2007.07.001

Cited by 144 publications

(82 citation statements)

References 57 publications

(34 reference statements)

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“…It remains to be elucidated whether the described bidirectional effects on connexin43 and N-cadherin expression in heterotypic cell pairs are the result of juxtacrine (cell contact mediated) and/or short-range paracrine signaling from the abutting cells. Furthermore, although a diffuse (dotted) pattern of connexin43 and N-cadherin has been previously reported in infarct border zones (30,40) and regions with implanted cells (10,46), further studies are warranted to investigate the precise distribution of coupling proteins at heterocellular interfaces within the heart.…”

Section: Discussionmentioning

confidence: 94%

Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay

Pedrotty¹,

Klinger²,

Badie³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Pedrotty DM, Klinger RY, Badie N, Hinds S, Kardashian A, Bursac N. Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay. Am J Physiol Heart Circ Physiol 295: H390 -H400, 2008. First published May 23, 2008; doi:10.1152 doi:10. /ajpheart.91531.2007controlled studies of the structural and functional interactions between cardiomyocytes and other cells are essential for understanding heart pathophysiology and for the further development of safe and efficient cell therapies. We established a novel in vitro assay composed of a large number of individual micropatterned cell pairs with reproducible shape, size, and region of cell-cell contact. This assay was applied to quantify and compare the frequency of expression and distribution of electrical (connexin43) and mechanical (N-cadherin) coupling proteins in 5,000 cell pairs made of cardiomyocytes (CMs), cardiac fibroblasts (CFs), skeletal myoblasts (SKMs), and mesenchymal stem cells (MSCs). We found that for all cell pair types, side-side contacts between two cells formed 4.5-14.3 times more often than end-end contacts. Both connexin43 and N-cadherin were expressed in all homotypic CM pairs but in only 13.4 -91.6% of pairs containing noncardiomyocytes, where expression was either junctional (at the site of cell-cell contact) or diffuse (inside the cytoplasm). CM expression was exclusively junctional in homotypic pairs but predominantly diffuse in heterotypic pairs. Noncardiomyocyte homotypic pairs exhibited diffuse expression 1.7-8.7 times more often than junctional expression, which was increased 2.6 -4.4 times in heterotypic pairs. Junctional connexin43 and N-cadherin expression, respectively, were found in 38.6 Ϯ 7.3 and 39.6 Ϯ 6.2% of CM-MSC pairs, 21.9 Ϯ 5.0 and 13.6 Ϯ 1.9% of CM-SKM pairs, and in only 3.8 -9.6% of CM-CF pairs. Measured frequencies of protein expression and distribution were stable for at least 4 days. Described studies in micropatterned cell pairs shed new light on cellular interactions relevant for cardiac function and cell therapies. micropatterning; coculture; stem cell; gap junction MYOCARDIAL INFARCTION RESULTS in an irreversible cardiomyocyte loss followed by replacement fibrosis and, often, progression to congestive heart failure. Cellular cardiomyoplasty, the transplantation of exogenous cells into the damaged heart, was recently proposed as an alternative approach for the treatment of postinfarction disease (35). Despite the initial promise of the transplantation of skeletal myoblasts and bone marrow-derived stem cells (1, 32), the latest results of double-blind placebocontrolled clinical trials have been more ambiguous (45). One main recognized obstacle to understanding the mechanisms of repair and designing more efficient therapies has been the difficulty in tracking and systematically studying the structural and functional interactions between the implanted cells and host cardiomyocytes in situ. Importantly, although a number of novel cardiogenic cell types a...

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Section: Discussionmentioning

confidence: 94%

Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay

Pedrotty¹,

Klinger²,

Badie³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…The mES and hES cell derived CMs form stable myocardial grafts in a variety of immuno-compromised animal hosts (Dai et al, 2007;Kehat et al, 2004;Klug et al, 1996;Laflamme et al, 2005) Moreover, hES derived CMs have been shown to restore function in cardiac damaged models. They improve contractility for the infarcted murine heart and provide pacing activity in pig hearts that have undergone atrioventricular node ablation (Cai et al, 2007a;Kehat et al, 2004).…”

Section: Clinical Applicationsmentioning

confidence: 99%

Directed Differentiation of Mesendoderm Derivatives from Embryonic Stem Cells

Gordillo¹,

Kumar²,

Turbendian³

et al. 2011

Embryonic Stem Cells: The Hormonal Regulation of Pluripotency and Embryogenesis

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“…This is perhaps not surprising, since the cells may represent the equivalent of early fetal cardiomyocytes, so it will be important to investigate the potential for further maturation in vitro. Nevertheless, several groups have shown that the cells survive when transplanted into rodent models and can improve function in the infracted rat heart [27,55,56], although further maturation or integration of the cells may be needed for long-term survival and successful therapy [57].…”

Section: Human Es-derived Cardiomyocytes and Ipsmentioning

confidence: 99%

Embryonic stem cells as a model for cardiac development and disease

Evans

2008

Drug Discovery Today: Disease Models

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SummaryThis review highlights recent progress in the use of embryonic stem cell (ESC) systems for studying and treating cardiovascular disease. Although ESCs represent an in vitro system, they can provide a rich source of progenitor cells, and this has been exploited recently to identify novel precursors and to investigate the lineage relationships among various cell types that comprise the developing heart, including cardiac muscle, endothelium, and smooth muscle. ESCs grown in aggregates (embryoid bodies) recapitulate normal developmental programs. Since they can be grown under defined culture conditions, they have been used to systematically identify specific genes and signaling pathways that promote cardiogenesis. A major goal is to optimize the production of cardiac progenitors and differentiated cell types, and to test their ability to promote healing in transplant assays, for example post-infarction. While many challenges remain, the development of iPS technology provides a means to generate cells for autologous transplant and for investigating patient-specific disease mechanisms. The development of new techniques to derive cardiac derivatives in vitro from ESC or iPS sources, coupled with novel tissue-engineering approaches and a better understanding of how explanted cells can survive and integrate in host tissue, should have a significant impact on the development of both cell-based and pharmacological therapies for cardiovascular disease. Keywords cardiogenesis; progenitors; cell therapies; iPSCan heart development and disease be studied in vitro?Organogenesis is a complex process that transforms relatively homogenous epithelial germ layers into functioning and highly integrated systems. From a developmental perspective, this can be viewed as a series of cellular transitions, including the commitment of progenitors to tissue-restricted fates, differentiation to express lineage-restricted genetic programs, morphogenesis to form appropriate tissue shapes, and system integration to incorporate the organ into the physiological state of the developing embryo. While the development of any organ system is remarkably complex, cardiogenesis requires extraordinary coordination of regulatory mechanisms in both time and space. In particular, both subtle and dramatic morphogenetic movements transform an initial primordial tube into a complex 3-dimensional organ consisting of septated chambers with distinct identities, a coronary vasculature and mature valves. Integration with both the venous and arterial systems must be timed perfectly 1300 York Ave. LC-709, New York, NY 10021, 212-746-5143, 212-746-8753 (fax), tre2003@med.cornell.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors...

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Survival and maturation of human embryonic stem cell-derived cardiomyocytes in rat hearts

Cited by 144 publications

References 57 publications

Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay

Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay

Directed Differentiation of Mesendoderm Derivatives from Embryonic Stem Cells

Embryonic stem cells as a model for cardiac development and disease

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