Angiogenic pretreatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation

Retuerto, Mauricio; Schalch, Don S.; Patejunas, Gerald; Carbray, JoAnn; Liu, Naxin; Esser, Karyn A.; Crystal, Ronald G.; Rosengart, Todd K.

doi:10.1016/j.jtcvs.2003.09.049

Cited by 70 publications

(51 citation statements)

References 30 publications

(63 reference statements)

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“…Although alteration of the environment in the recipient infarct region into which the cells are grafted might improve the survival of implanted cells (20), increased cellular tolerance to ischemia may be more beneficial. The induction of angiogenesis in the infarct region before implantation of cells was associated with only a modest improvement in ventricular function (21).…”

Section: Discussionmentioning

confidence: 99%

Enhanced cell transplantation: preventing apoptosis increases cell survival and ventricular function

Nakamura¹,

Yasuda²,

Weisel³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Cell transplantation prevents cardiac dysfunction after myocardial infarction. However, because most implanted cells are lost to ischemia and apoptosis, the benefits of cell transplantation on heart function could be improved by increasing cell survival. To examine this possibility, male Lewis rat aortic smooth muscle cells (SMCs; 4 ϫ 10 6 ) were pretreated with antiapoptotic Bcl-2 gene transfection or heat shock and then implanted into the infarcted myocardium of anesthetized, syngenic female rats (n ϭ 23 per group). On the first day after transplantation, apoptotic SMCs were quantified by using transferase-mediated dUTP nick-end labeling staining. On days 7 and 28, grafted cell survival was quantified by using real-time PCR, and heart function was assessed with the use of echocardiographyandtheLangendorffapparatus.SMCsgivenantiapoptotic pretreatments exhibited improvements in each measure relative to controls. Apoptosis was reduced in Bcl-2-treated cells relative to all other groups (P Ͻ 0.05), whereas survival (P Ͻ 0.01) was increased. Heat shock also significantly decreased apoptosis and increased survival relative to control groups (P Ͻ 0.05 for group effect), although these effects were less pronounced than in the Bcl-2-treated group. Further, scar areas were reduced in both Bcl-2-and heat shock-treated groups relative to controls (P Ͻ 0.05), and fractional area change and cardiac function were greater (P Ͻ 0.05 for both measures). These results indicate that antiapoptosis pretreatments reduced grafted SMC loss after transplantation and enhanced grafted cell survival and ventricular function, which was directly related (r ϭ 0.72; P ϭ 0.002) to the number of surviving engrafted cells. cell therapy; Bcl-2; heat shock; ventricular modulation; angiogenesis SKELETAL MYOBLAST TRANSPLANTATION prevents scar thinning and ventricular dilatation after a myocardial infarction and has been associated with improved regional and global function in both animal experimentation (5,17,26) and the initial clinical trials of this intervention (6, 15). The mechanism responsible for this beneficial effect has not been elucidated but may include angiogenesis, altering the elasticity of the ventricular wall, and/or modifying matrix remodeling. These mechanisms were suggested because none of the myriad of implanted cells have been demonstrated to differentiate into functioning cardiomyocytes, nor have they been demonstrated to beat synchronously with the remaining recipient cardiomyocytes. Therefore, the goal of cell transplantation is to establish a graft of viable cells within the infarct region to modify ventricular remodeling and prevent congestive heart failure. If the grafted cells could contribute to the contractility of the infarct scar, the beneficial effect would be enhanced. In the present study, our first aim was to evaluate the efficacy of smooth muscle cell (SMC) transplantation to augment cardiac function, because these cells routinely induce angiogenesis and matrix remodeling and might be ideally suited to efficient...

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Section: Discussionmentioning

confidence: 99%

Enhanced cell transplantation: preventing apoptosis increases cell survival and ventricular function

Nakamura¹,

Yasuda²,

Weisel³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…One approach to this challenge is a two-stage process, where pro-vascularization interventions are employed initially, followed by seeding of a myogenic population. In any case, vascularization is clearly required for long term graft survival, and several studies have found over-expression of vascular endothelial growth factor (VEGF) enhances grafted cell survival [74][75][76]. Interestingly, adenoviral over-expression of hypoxia inducible factor-1α (HIF-1α) [77] with grafted skeletal myoblasts increased graft cell number, blood vessel formation and cardiac function.…”

Section: Strategies To Increase Cell Survivalmentioning

confidence: 99%

Systems approaches to preventing transplanted cell death in cardiac repair

Robey

Saiget

Reinecke

et al. 2008

Journal of Molecular and Cellular Cardiology

364

294

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Stem cell transplantation may repair the injured heart, but tissue regeneration is limited by death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, anoikis and inflammation. Interventions known to enhance transplanted cell survival include heat shock, over-expressing anti-apoptotic proteins, free radical scavengers, anti-inflammatory therapy and co-delivery of extracellular matrix molecules. Combinatorial use of such interventions markedly enhances graft cell survival, but death still remains a significant problem. We review these challenges to cardiac cell transplantation and present an approach to systematically address them.Most anti-death studies use histology to assess engraftment, which is time-and labor-intensive. To increase throughput, we developed two biochemical approaches to follow graft viability in the mouse heart. The first relies on LacZ enyzmatic activity to track genetically modified cells, and the second quantifies human genomic DNA content using repetitive Alu sequences. Both show linear relationships between input cell number and biochemical signal, but require correction for the time lag between cell death and loss of signal. Once optimized, they permit detection of as few as 1 graft cell in 40,000 host cells. Pro-survival effects measured biochemically at three days predict long-term histological engraftment benefits. These methods permitted identification of carbamylated erythropoietin (CEPO) as a pro-survival factor for human embryonic stem cell-derived cardiomyocyte grafts. CEPO's effects were additive to heat shock, implying independent survival pathways. This system should permit combinatorial approaches to enhance graft viability in a fraction of the time required for conventional histology.

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“…Recipient ischemic tissue may be inadequate for donor cell retention in sufficient quantity to allow for the desired effect, because the survival of cells from any source implanted in the myocardium varies between 1% and 10%. 11 Also, nonspecific delivery of donor cells to other body sites constitutes an unwanted potential side effect. Cell-based angiogenesis may therefore benefit from tissue engineered strategies to better administer cells and optimize their specific homing.…”

mentioning

confidence: 99%

Tissue-Engineered Injectable Collagen-Based Matrices for Improved Cell Delivery and Vascularization of Ischemic Tissue Using CD133 ⁺ Progenitors Expanded From the Peripheral Blood

et al. 2006

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Background-The use of stem and/or progenitor cells to achieve potent vasculogenesis in humans has been hindered by low cell numbers, implant capacity, and survival. This study investigated the expansion of CD133 ϩ cells and the use of an injectable collagen-based tissue engineered matrix to support cell delivery and implantation within target ischemic tissue. Methods and Results-Adult human CD133ϩ progenitor cells from the peripheral blood were generated and expanded by successive removal and culture of CD133 Ϫ cell fractions, and delivered within an injectable collagen-based matrix into the ischemic hindlimb of athymic rats. Controls received injections of phosphate-buffered saline, matrix, or CD133

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Angiogenic pretreatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation

Abstract: Pretreatment of an infarcted region of the heart with angiogenic mediators such as VEGF can enhance the efficacy of cellular cardiomyoplasty, presumably by creating a more favorable environment for the survival of transplanted cells.

Cited by 70 publications

References 30 publications

Enhanced cell transplantation: preventing apoptosis increases cell survival and ventricular function

Enhanced cell transplantation: preventing apoptosis increases cell survival and ventricular function

Systems approaches to preventing transplanted cell death in cardiac repair

Tissue-Engineered Injectable Collagen-Based Matrices for Improved Cell Delivery and Vascularization of Ischemic Tissue Using CD133 ⁺ Progenitors Expanded From the Peripheral Blood

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Angiogenic pretreatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation

Abstract: Pretreatment of an infarcted region of the heart with angiogenic mediators such as VEGF can enhance the efficacy of cellular cardiomyoplasty, presumably by creating a more favorable environment for the survival of transplanted cells.

Cited by 70 publications

References 30 publications

Enhanced cell transplantation: preventing apoptosis increases cell survival and ventricular function

Enhanced cell transplantation: preventing apoptosis increases cell survival and ventricular function

Systems approaches to preventing transplanted cell death in cardiac repair

Tissue-Engineered Injectable Collagen-Based Matrices for Improved Cell Delivery and Vascularization of Ischemic Tissue Using CD133 + Progenitors Expanded From the Peripheral Blood

Contact Info

Product

Resources

About

Tissue-Engineered Injectable Collagen-Based Matrices for Improved Cell Delivery and Vascularization of Ischemic Tissue Using CD133 ⁺ Progenitors Expanded From the Peripheral Blood