Cardiac Repair by Embryonic Stem-Derived Cells

Rubart, Michael; Field, Loren J.

doi:10.1007/978-3-540-77855-4_4

Cited by 15 publications

(20 citation statements)

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“…Stochastic inductive cues occurring within the embryoid bodies promote differentiation, and cell types deriving from all 3 embryonic lineages typically appear, including spontaneously contracting cardiomyocytes. Similar results are observed with mouse [Doetschman et al, 1985] and human [Kehat et al, 2001, Mummery et al, 2002 ESCs, and numerous studies have shown that ESCs generate bona fide cardiomyocytes with attributes of the atrial, ventricular or conducting myocardium [for review, see Rubart et al, 2006]. Interestingly, an ESC-like cell with cardiomyogenic potential was recently obtained from cultured spermatogonial stem cells [Guan et al, 2006].…”

Section: Embryonic Stem Cell-derived Cardiomyocytessupporting

confidence: 65%

“…Murine ESC-derived cardiomyocytes were also enriched via fluorescence-activated cell sorting following transfection of a lineage-restricted fluorescence reporter [Muller et al, 2000], an approach which has recently been shown to work with human ESCs [Huber et al, 2007]. Considerable effort has also been invested in identifying combinatorial growth factor treatments which enhance cardiomyogenic differentiation (and consequently, yield) in ESC cultures [for review, see Rubart et al, 2006]. Interestingly, recent studies have shown that both vascular cells and cardiomyocytes arise from a common progenitor cell in differentiating ESC cultures [Kattman et al, 2006;Moretti et al, 2006;Wu et al, 2006], raising the possibility that transplantation of such cells might result in restoration of contractile cell mass as well as enhanced perfusion of the graft.…”

Section: Embryonic Stem Cell-derived Cardiomyocytesmentioning

confidence: 99%

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Stem Cell Differentiation: Cardiac Repair

Rubart

Field

2007

Cells Tissues Organs

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Cellular transplantation has been employed for several years to deliver donor cardiomyocytes to normal and injured hearts. Recent reports of a variety of stem cells with apparent cardiomyogenic potential have raised the possibility of cell transplantation-based therapeutic interventions for heart disease. Here we review the preclinical studies demonstrating that intracardiac transplantation of skeletal myoblasts, cardiomyocytes and cardiomyogenic stem cells is feasible. In addition, recent clinical studies of skeletal myoblast and adult stem cell transplantation for heart disease are discussed.

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Section: Embryonic Stem Cell-derived Cardiomyocytessupporting

confidence: 65%

Section: Embryonic Stem Cell-derived Cardiomyocytesmentioning

confidence: 99%

Stem Cell Differentiation: Cardiac Repair

Rubart

Field

2007

Cells Tissues Organs

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“…Given these attributes, it is not surprising that a number of groups have utilized either mouse [reviewed in 4 ] or hESC-derived cardiomyocytes as donor cells in transplantation studies. In the case of hESCs, Kehat and colleagues micro-dissected contracting regions of adherent EBs and injected them into immune suppressed pigs with experimental heart block [5].…”

Section: Discussionmentioning

confidence: 99%

“…Although numerous studies have examined the fate and consequences of murine ESC-derived cardiomyocyte transplantation [4], only a limited number of studies examining transplantation of hESC-derived cardiomyocytes have been reported. These studies [5 , 6, 7 ] used hESC-derived cardiomyocytes generated locally or regionally, a situation that would unlikely be the case in a clinical setting.…”

Section: Introductionmentioning

confidence: 99%

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

Dai

Field

Rubart

et al. 2007

Journal of Molecular and Cellular Cardiology

144

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Purpose-Human embryonic stem cell (hESC)-derived cardiomyocytes are a promising cell source for cardiac repair. Whether these cells can be transported long distance, survive, and mature in hearts subjected to ischemia/reperfusion with minimal infarction is unknown. Taking advantage of a constitutively GFP-expressing hESC line we investigated whether hESC-derived cardiomyocytes could be shipped and subsequently form grafts when transplanted into the left ventricular wall of athymic nude rats subjected to ischemia/reperfusion with minimal infarction. Co-localization of GFP-epifluorescence and cardiomyocyte specific marker staining was utilized to analyze hESCderived cardiomyocyte fate in a rat ischemia/reperfused myocardium.Methods-Differentiated, constitutively green fluorescent protein (GFP) expressing hESCs (HES3-GFP; Envy) containing about 13% cardiomyocytes were differentiated in Singapore, and shipped in culture medium at 4°C to Los Angeles (shipping time ~3 days). The cells were dissociated and a cell suspension (2×10 6 cells for each rat, n=10) or medium (n=10) was injected directly into the myocardium within the ischemic risk area 5 minutes after left coronary artery occlusion in athymic nude rats. After 15 minutes of ischemia the coronary artery was reperfused. The hearts were harvested at various time points later and processed for histology, immunohistochemical staining, and fluorescence microscopy. In order to assess whether the hESC-derived cardiomyocytes might evade immune surveillance, 2×10 6 cells were injected into immune competent Sprague-Dawley rat hearts (n=2), and the hearts were harvested at 4 weeks after cell injection and examined as in the previous procedures.Results-Even following 3 days of shipping, the hESC-derived cardiomyocytes within embryoid bodies (EBs) showed active and rhythmic contraction after incubation in the presence of 5% CO 2 at 37°C. In the nude rats, following cell implantation, H&E, immunohistochemical staining and GFP epifluorescence demonstrated grafts in 9 out of 10 hearts. Cells that demonstrated GFP epifluorescence also stained positive (co-localized) for the muscle marker alpha-actinin and exhibited cross striations (sarcomeres). Furthermore cells that stained positive for the antibody to GFP (immunohistochemistry) also stained positive for the muscle marker sarcomeric actin and Conclusions-hESCs-derived cardiomyocytes can survive several days of shipping. Grafted cells survived up to 4 weeks after transplantation in hearts of nude rats subjected to ischemia/reperfusion with minimal infarction. They continued to express cardiac muscle markers, exhibit sarcomeric structure, and were well interspersed with the endogenous myocardium. However, hESC-derived cells did not escape immune surveillance in the xenograft setting in that they elicited a rejection phenomenon in immune competent rats.

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“…Similarly and analogous to mouse ES cells, no single transcription factor or signaling pathway directs hES cells exclusively into a heart cell, suggesting that multiple signals and/or pathways must be involved in the commitment of pluripotent cells to cardiomyocytes. Importantly and when tested for cell-to-cell functional coupling, ES cell-derived CMs from both human and mouse integrate and functionally couple in adult myocardium [42,43].…”

Section: Embryonic Stem Cells and Cardiomyogenesismentioning

confidence: 99%

Cardiomyogenic stem and progenitor cell plasticity and the dissection of cardiopoiesis

Perino¹,

Yamanaka²,

Li³

et al. 2008

Journal of Molecular and Cellular Cardiology

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Cell based therapies hold promise of repairing an injured heart, and the description of stem and progenitor cells with cardiomyogenic potential is critical to its realization. At the vanguard of these efforts are analyses of embryonic stem cells, which clearly have the capacity to generate large numbers of cardiomyocytes in vitro. Through the use of this model system, a number of signaling mechanisms have been worked out that describes at least partially the process of cardiopoiesis. Studies on adult stem and on progenitor cells with cardiomyogenic potential are still in their infancy, and much less is known about the molecular signals that are required to induce the differentiation to cardiomyocytes. It is also unclear whether the pathways are similar or different between embryonic and adult cell-induced cardiomyogenesis, partly because of the continued controversies that surround the stem cell theory of cardiac self-renewal. Irrespective of any perceived or actual limitations, the study of stem and progenitor cells has provided important insights into the process of cardiomyogenesis, and it is likely that future research in this area will turn the promise of repairing an injured heart into a reality.

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Cardiac Repair by Embryonic Stem-Derived Cells

Cited by 15 publications

References 0 publications

Stem Cell Differentiation: Cardiac Repair

Stem Cell Differentiation: Cardiac Repair

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

Cardiomyogenic stem and progenitor cell plasticity and the dissection of cardiopoiesis

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