A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction

Freyman, Toby; Polin, Glenn M.; Osman, Hashim; Crary, Jody; Lü, Minmin; Cheng, Lan; Palasis, Maria; Wilensky, Robert L.

doi:10.1093/eurheartj/ehi818

Cited by 560 publications

(454 citation statements)

References 30 publications

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“…Intracoronary infusion of MSCs may cause distal embolization and consequent no-reflow phenomena. Freyman et al 29 reported that intracoronary MSC infusion impaired coronary flow distal to the infusion site in half of their treated pigs. Similar to this report, the intracoronary administration showed elevated cardiac enzymes and micro infarctions in dogs with normal coronary arteries.…”

Section: Discussionmentioning

confidence: 98%

Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization

Sato

Iso

Uyama

et al. 2011

Laboratory Investigation

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Few reports have examined the effects of adult bone marrow multipotent stromal cells (MSCs) on large animals, and no useful method has been established for MSC implantation. In this study, we investigate the effects of MSC infusion from the coronary vein in a swine model of chronic myocardial infarction (MI). MI was induced in domestic swine by placing beads in the left coronary artery. Bone marrow cells were aspirated and then cultured to isolate the MSCs. At 4 weeks after MI, MSCs labeled with dye (n ¼ 8) or vehicle (n ¼ 5) were infused retrogradely from the anterior interventricular vein without any complications. Left ventriculography (LVG) was performed just before and at 4 weeks after cell infusion. The ejection fraction (EF) assessed by LVG significantly decreased from baseline up to a follow-up at 4 weeks in the control group (Po0.05), whereas the cardiac function was preserved in the MSC group. The difference in the EF between baseline and follow-up was significantly greater in the MSC group than in the control group (Po0.05). The MSC administration significantly promoted neovascularization in the border areas compared with the controls (Po0.0005), though it had no affect on cardiac fibrosis. A few MSCs expressed von Willebrand factor in a differentiation assay, but none of them expressed troponin T. In quantitative gene expression analysis, basic fibroblast growth factor and vascular endothelial growth factor (VEGF) levels were significantly higher in the MSC-treated hearts than in the controls (Po0.05, respectively). Immunohistochemical staining revealed VEGF production in the engrafted MSCs. In vitro experiment demonstrated that MSCs significantly stimulated endothelial capillary network formation compared with the VEGF protein (Po0.0001). MSC infusion via the coronary vein prevented the progression of cardiac dysfunction in chronic MI. This favorable effect appeared to derive not from cell differentiation, but from enhanced neovascularization by angiogenic factors secreted from the MSCs.

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Section: Discussionmentioning

confidence: 98%

Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization

Sato

Iso

Uyama

et al. 2011

Laboratory Investigation

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“…Indeed, despite its potential benefits, cell transplantation is limited in its clinical applications. It has been established that only ∼5% of mesenchymal stem cells, which are one of the best candidates for cell therapy in heart diseases, can survive for 14 days in the infarcted porcine heart [164]. In addition, the survival rate of transplanted human mesenchymal stem cells in a mouse heart reaches <0.5% at 4 days after transplantation [165].…”

Section: Cell-based Therapies and Anoikismentioning

confidence: 99%

Anoikis: an emerging hallmark in health and diseases

Taddei

Giannoni

Fiaschi

et al. 2011

The Journal of Pathology

527

404

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Anoikis is a programmed cell death occurring upon cell detachment from the correct extracellular matrix, thus disrupting integrin ligation. It is a critical mechanism in preventing dysplastic cell growth or attachment to an inappropriate matrix. Anoikis prevents detached epithelial cells from colonizing elsewhere and is thus essential for tissue homeostasis and development. As anchorage-independent growth and epithelial-mesenchymal transition, two features associated with anoikis resistance, are crucial steps during tumour progression and metastatic spreading of cancer cells, anoikis deregulation has now evoked particular attention from the scientific community. The aim of this review is to analyse the molecular mechanisms governing both anoikis and anoikis resistance, focusing on their regulation in physiological processes, as well as in several diseases, including metastatic cancers, cardiovascular diseases and diabetes.

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“…Using smooth muscle cells Yasuda et al reported viable graft cell counts of 15% at 1 week and 9% at 4 weeks after permanent LAD ligation in a rat infarction model [13,42]. Similarly, Hayashi et al reported that 6% of unfractionated bone marrow cells survived at 3 days in infarcted rat [13,42], and Freyman et al reported that ~5% of mesenchymal stem cells survived after transplanting into the infarcted porcine heart [43]. Clearly, there is considerable room for improvement, and solving the problem of cell death is central to successful remuscularization of the infarcted heart.…”

Section: Introductionmentioning

confidence: 99%

Systems approaches to preventing transplanted cell death in cardiac repair

Robey

Saiget

Reinecke

et al. 2008

Journal of Molecular and Cellular Cardiology

367

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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A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction

Cited by 560 publications

References 30 publications

Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization

Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization

Anoikis: an emerging hallmark in health and diseases

Systems approaches to preventing transplanted cell death in cardiac repair

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