Positron emission tomography based in-vivo imaging of early phase stem cell retention after intramyocardial delivery in the mouse model

Lang, Cajetan Immanuel; Lehner, S.; Todica, Andrei; Boening, Guido; Franz, Wolfgang-Michael; Bartenstein, Peter; Hacker, Marcus; Dávid, Róbert

doi:10.1007/s00259-013-2480-1

Cited by 26 publications

(19 citation statements)

References 42 publications

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“…The imaging technique enabled us to illustrate how particles were drained from the injection site to the right atrium, a mechanism that also explains pulmonary accumulation of injected microspheres when injections are performed in beating hearts. This amount of loss was similar to what has been shown in cellular experiments [18]. In order to ensure that macroscopic fluorescence imaging was capable of detecting the total amount of microspheres contained in each organ, quantifications were also performed after a tissue reduction process.…”

Section: Discussionsupporting

confidence: 66%

“…For this purpose, imaging techniques that evaluate cell fate in vivo are essential. However, quantifying cell retention in myocardial tissue involves time consuming processing and generally require expensive imaging methods such as positron emission tomography (PET), magnetic resonance imaging (MRI) or computerized tomography (CT) [16]–[18], [27], [28]. Additionally, millions of trackable cells need to be produced for every experiment, which adds further costs and complexity to the experimental setting.…”

Section: Introductionmentioning

confidence: 99%

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Macroscopic Fluorescence Imaging: A Novel Technique to Monitor Retention and Distribution of Injected Microspheres in an Experimental Model of Ischemic Heart Failure

et al. 2014

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BackgroundThe limited effectiveness of cardiac cell therapy has generated concern regarding its clinical relevance. Experimental studies show that cell retention and engraftment are low after injection into ischemic myocardium, which may restrict therapy effectiveness significantly. Surgical aspects and mechanical loss are suspected to be the main culprits behind this phenomenon. As current techniques of monitoring intramyocardial injections are complex and time-consuming, the aim of the study was to develop a fast and simple model to study cardiac retention and distribution following intramyocardial injections. For this purpose, our main hypothesis was that macroscopic fluorescence imaging could adequately serve as a detection method for intramyocardial injections.Methods and ResultsA total of 20 mice underwent ligation of the left anterior descending artery (LAD) for myocardial infarction. Fluorescent microspheres with cellular dimensions were used as cell surrogates. Particles (5×105) were injected into the infarcted area of explanted resting hearts (Ex vivo myocardial injetions EVMI, n = 10) and in vivo into beating hearts (In vivo myocardial injections IVMI, n = 10). Microsphere quantification was performed by fluorescence imaging of explanted organs. Measurements were repeated after a reduction to homogenate dilutions. Cardiac microsphere retention was 2.78×105±0.31×105 in the EVMI group. In the IVMI group, cardiac retention of microspheres was significantly lower (0.74×105±0.18×105; p<0.05). Direct fluorescence imaging revealed venous drainage through the coronary sinus, resulting in a microsphere accumulation in the left (0.90×105±0.20×105) and the right (1.07×105±0.17×105) lung. Processing to homogenates involved further particle loss (p<0.05) in both groups.ConclusionsWe developed a fast and simple direct fluorescence imaging method for biodistribution analysis which enabled the quantification of fluorescent microspheres after intramyocardial delivery using macroscopic fluorescence imaging. This new technique showed massive early particle loss and venous drainage into the right atrium leading to substantial accumulation of graft particles in both lungs.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Macroscopic Fluorescence Imaging: A Novel Technique to Monitor Retention and Distribution of Injected Microspheres in an Experimental Model of Ischemic Heart Failure

et al. 2014

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“…However, the retrieved eGFP+ cell number was very low and no injected cells were found 48 h after implantation using immunohistochemistry. Cell retention is limited by 1) the immediate washout following injection and thereafter because of 2) the hostile environment offered in the infarcted area, which lacks supporting cells or tissues, oxygen or nutritive substrates, but contains an excess of neutrophils and scavenger cells [31,42,43]. However, it has to be pointed out that CD117 + BMSC display inconsistent eGFP expression in the investigated transgenic mice strain, which further hampers cell retention analysis.…”

Section: Discussionmentioning

confidence: 99%

Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy

Ludwig¹,

Tölk²,

Skorska³

et al. 2015

Cell Physiol Biochem

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Background/Aims: CD117⁺ stem cell (SC) based therapy is considered an alternative therapeutic option for terminal heart disease. However, controversies exist on the effects of CD117⁺ SC implantation. In particular, the link between CD117⁺ SC function and angiotensin-II-type-2 receptor (AT2R) after MI is continuously discussed. We therefore asked whether 1) AT2R stimulation influences CD117⁺ SC properties in vitro and, 2) which effects can be ascribed to AT2R stimulation in vivo. Methods: We approached AT2R stimulation with Angiotensin II while simultaneously blocking its opponent receptor AT1 with Losartan. CD117 effects were dissected using a 2D-Matrigel assay and HL-1 co-culture in vitro. A model of myocardial infarction, in which we implanted EGFP+ CD117 SC, was further applied. Results: While we found indications for AT2R driven vasculogenesis in vitro, co-culture experiments revealed that CD117⁺ SC improve vitality of cardiomyocytes independently of AT2R function. Likewise, untreated CD117⁺ SC had a positive effect on cardiac function and acted cardioprotective in vivo. Conclusions: Therefore, our data show that transient AT2R stimulation does not significantly add to the beneficial actions of CD117⁺ SC in vivo. Yet, exploiting AT2R driven vasculogenis via an optimized AT2R stimulation protocol may become a promising tool for cardiac SC therapy.

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“…The success of SC therapy correleates with the number of cells retained at the site of injection [459]. Since the heart is a higly perfused organ, 90 -99% of transplanted cells are typically lost within the first 1 to 2 hours [460][461][462][463][464]. Magnetic cell targeting techniques facilitate guidance of transplanted cells to the site of interest and improve cell retention [465].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

Müller

Lemcke

Dávid

2018

Cell Physiol Biochem

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174

140

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A large number of clinical trials have shown stem cell therapy to be a promising therapeutic approach for the treatment of cardiovascular diseases. Since the first transplantation into human patients, several stem cell types have been applied in this field, including bone marrow derived stem cells, cardiac progenitors as well as embryonic stem cells and their derivatives. However, results obtained from clinical studies are inconsistent and stem cell-based improvement of heart performance and cardiac remodeling was found to be quite limited. In order to optimize stem cell efficiency, it is crucial to elucidate the underlying mechanisms mediating the beneficial effects of stem cell transplantation. Based on these mechanisms, researchers have developed different improvement strategies to boost the potency of stem cell repair and to generate the “next generation” of stem cell therapeutics. Moreover, since cardiovascular diseases are complex disorders including several disease patterns and pathologic mechanisms it may be difficult to provide a uniform therapeutic intervention for all subgroups of patients. Therefore, future strategies should aim at more personalized SC therapies in which individual disease parameters influence the selection of optimal cell type, dosage and delivery approach.

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Positron emission tomography based in-vivo imaging of early phase stem cell retention after intramyocardial delivery in the mouse model

Cited by 26 publications

References 42 publications

Macroscopic Fluorescence Imaging: A Novel Technique to Monitor Retention and Distribution of Injected Microspheres in an Experimental Model of Ischemic Heart Failure

Macroscopic Fluorescence Imaging: A Novel Technique to Monitor Retention and Distribution of Injected Microspheres in an Experimental Model of Ischemic Heart Failure

Exploiting AT2R to Improve CD117 Stem Cell Function In Vitro and In Vivo - Perspectives for Cardiac Stem Cell Therapy

Stem Cell Therapy in Heart Diseases – Cell Types, Mechanisms and Improvement Strategies

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