Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype

Rangappa, Sunil; Entwistle, John W.; Wechsler, Andrew S.; Kresh, J. Yasha

doi:10.1016/s0022-5223(03)00074-6

Cited by 162 publications

(100 citation statements)

References 21 publications

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“…It apparently acts by modifying methylation [Momparler, 2005]. Other experiments studied coculture model of MSCs with neonatal cardiomyocytes [Lagostena et al, 2005] or cardiomyocyte-cell lines [Rangappa et al, 2003;Beeres et al, 2005], but not extensively with primary adult cardiomyocytes. We are presenting a study in controlled conditions of the effect of adult cardiomyocytes on the expression of markers of differentiation in MSCs.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, regarding heart repair, they have been shown to potentially originate both endothelial vascular cells and cardiomyocytes. Among the different strategies proposed to promote in vitro cardiac differentiation of MSCs, chronic exposure to 5-azacytidine has been amply tested [reviewed by Leri et al, 2005], as well as stimulation by exogenous cytokines and growth factors [Xaymardan et al, 2004, Shim et al, 2004, and coculture with neonatal cardiac cell [Lagostena et al, 2005] or immortalized cardiac cell lines [Rangappa et al, 2003]. Cocultures between MSCs and adult cardiomyocytes were performed mainly to show functional connection between the two cell types [Valiunas et al, 2004].…”

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confidence: 99%

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Limited plasticity of mesenchymal stem cells cocultured with adult cardiomyocytes

Gallo¹,

Ramella²,

Alloatti³

et al. 2006

J of Cellular Biochemistry

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In order to assess, in a controlled in vitro model, the differentiation potential of adult bone marrow derived stem cells we have developed a coculture procedure using adult rat cardiomyocytes and mesenchymal stem cells (MSCs) from transgenic GFP positive rats. We investigated in the cocultured MSCs the time course of cellular processes that are difficult to monitor in in vivo experiments. Adult rat cardiomyocytes and adult rat MSCs were cocultured for up to 7 days and analyzed by confocal microscopy. Several markers were studied by immunofluorescence technique. The fluorescent ST-BODIPY-Dihydropyridine was used to label calcium channels in living cells. Intracellular calcium was monitored with the fluorescent probe X-Rhod-1. Immunofluorescence experiments showed the presence of connexin-43 between cardiomyocytes and MSCs and between MSCs, while no sarcomeric structures were observed at any time of the coculture. We looked at the expression of calcium channels and development of voltage-dependent calcium signaling in cocultured MSCs. MSCs showed a time-dependent increase of labeling of ST-BODIPY-Dihydropyridine, reaching a relatively strong level after 72 h of coculture. The treatment with a non-fluorescent DHP, Nifedipine, completely abolished ST-BODIPY labeling. We investigated whether depolarization could modulate intracellular calcium. Depolarization-induced calcium transients increased in MSCs in relation to the coculture time. We conclude that MSCs cocultured with adult cardiomyocytes present preliminary evidence of voltage-dependent calcium modulation uncoupled with the development of nascent or adult myofibrils, thus showing a limited lineage specification and a low plasticity to differentiate in a full cardiomyocyte-like phenotype.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Limited plasticity of mesenchymal stem cells cocultured with adult cardiomyocytes

Gallo¹,

Ramella²,

Alloatti³

et al. 2006

J of Cellular Biochemistry

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“…It has also been demonstrated that BMSCs can differentiate into cardiac cell components and develop into functional phenotypes of myocardial cells within the microenvironment of the heart. 4 -6 Human mesenchymal stem cells cocultured with myocytes express myosin heavy chain, ␤-actin, and troponin T. 7 BMSCs can not only differentiate into myocytes but also improve left ventricular performance 8 and cause a significant reduction of infarct size when injected into the infarcted hearts or border zones of rats or mice. 5,6,9 Moreover, BMSCs can be delivered into the coronary artery, because they are capable of targeted migration and differentiation into cardiomyocytes in the scar tissue to improve cardiac function.…”

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confidence: 99%

Differentiation of Bone Marrow Stromal Cells Into the Cardiac Phenotype Requires Intercellular Communication With Myocytes

et al. 2004

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Background-Bone marrow stromal cells (BMSCs) have the potential to differentiate into various cells and can transdifferentiate into myocytes if an appropriate cellular environment is provided. However, the molecular signals that underlie this process are not fully understood. In this study, we show that BMSC differentiation is dependent on communication with cells in their microenvironment. Methods and Results-BMSCs were isolated from green fluorescent protein (GFP)-transgenic mice and cocultured with myocytes in a ratio of 1:40. Myocytes were obtained from neonatal rat ventricles. The differentiation of BMSCs in coculture was confirmed by immunohistochemistry, electron microscopy, and reverse transcription-polymerase chain reaction. Before coculturing, the BMSCs were negative for ␣-actinin and exhibited a nucleus with many nucleoli. After 7-day coculture with myocytes, some BMSCs became ␣-actinin-positive and formed gap junctions with native myocytes. However, BMSCs separated from myocytes by a semipermeable membrane were still negative for ␣-actinin.

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“…Despite these differences in origin, several studies show that bone marrow-derived mesenchymal progenitor cells can acquire a cardiomyocyte phenotype under certain conditions in vitro and in vivo. These cells are capable of differentiating into cells with cardiomyocyte features in vitro, either through coculture with cardiomyocytes 44 or exposure to 5-azacytidine, 45 a cysteine analog capable of altering the expression of certain genes that may regulate differentiation. The cells are positive for b-myosin heavy chain, cardiac troponin T, a-cardiac actin and desmin.…”

Section: Mesenchymal Progenitor Cellsmentioning

confidence: 99%

Progress and prospects: Cell based regenerative therapy for cardiovascular disease

2005

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Experimental and clinical studies are progressing simultaneously to investigate the mechanisms and efficacy of progenitor cell treatment after an acute myocardial infarction and in chronic congestive heart failure. Multipotent progenitor cells appear to be capable of improving cardiac perfusion and/or function; however, the mechanisms still are unclear, and the issue of whether or not trans-differentiation occurs remains unsettled. Both experimentally and clinically, cells originating from different tissues have been shown capable of restoring cardiac function, but more recently multiple groups have identified resident cardiac progenitor cells that seem to participate in regenerating the heart after injury. Clinically, cells originating from blood or bone marrow have been proven to be safe whereas injection of skeletal myoblasts has been associated with the occurrence of ventricular arrhythmias. Myoblasts can transform into rapidly beating myotubes; however, thus far convincing evidence for electro-mechanical coupling between myoblasts and cardiomyocytes is lacking. Moving forward, mechanistic studies will benefit from the use of genetic markers and Cre/lox reporter systems that are less prone to misinterpretation than fluorescent antibodies, and a more convincing answer regarding therapeutic efficacy will come from adequately powered randomized placebo controlled trials. Gene Therapy (2006) 13, 659-671.

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Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype

Cited by 162 publications

References 21 publications

Limited plasticity of mesenchymal stem cells cocultured with adult cardiomyocytes

Limited plasticity of mesenchymal stem cells cocultured with adult cardiomyocytes

Differentiation of Bone Marrow Stromal Cells Into the Cardiac Phenotype Requires Intercellular Communication With Myocytes

Progress and prospects: Cell based regenerative therapy for cardiovascular disease

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