In vivo MR imaging of magnetically labeled human embryonic stem cells

Tallheden, Tommi; Nannmark, Ulf; Lorentzon, Mattias; Rakotonirainy, Olivier; Soussi, B.; Waagstein, Finn; Jeppsson, Anders; Sjögren‐Jansson, Eva; Lindahl, Anders; Ömerovic, Elmir

doi:10.1016/j.lfs.2006.05.021

Cited by 63 publications

(45 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, consistent with our findings, other groups have reported signal attenuation (ranging from 30% to 60%), cell migration, and cell loss at varying time points after transplantation [8,14,31,35].…”

Section: Discussionsupporting

confidence: 92%

“…The success of preclinical studies has partially relied on the use of appropriate large animals to establish reliable models for cellular transplantation [1][2][3][4][5]. Stem cell-based therapies in small animal models have yielded promising but variable results [6][7][8]. Several studies have supported the use of large animals, such as pigs, with a similar heart size and physiology to humans, to monitor the survival, engraftment, and efficacy of transplanted hESC-derived cardiac cells [2][3][4][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Despite promising advances in cell labeling [6][7][8][13][14][15][16][17], no single method to date has yielded a nontoxic, readily accessible, and accurate system for longitudinal monitoring of transplanted cells in the heart. Superparamagnetic iron oxide nanoparticles (SPIOs) are well characterized and widely used cell-labeling agents for magnetic resonance imaging (MRI) [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Magnetic Resonance Imaging of Iron Oxide-Labeled Human Embryonic Stem Cell-Derived Cardiac Progenitors

Skelton

Khoja

Almeida

et al. 2015

Stem Cells Translational Medicine

View full text Add to dashboard Cite

Given the limited regenerative capacity of the heart, cellular therapy with stem cell-derived cardiac cells could be a potential treatment for patients with heart disease. However, reliable imaging techniques to longitudinally assess engraftment of the transplanted cells are scant. To address this issue, we used ferumoxytol as a labeling agent of human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs) to facilitate tracking by magnetic resonance imaging (MRI) in a large animal model. Differentiating hESCs were exposed to ferumoxytol at different time points and varying concentrations. We determined that treatment with ferumoxytol at 300 mg/ml on day 0 of cardiac differentiation offered adequate cell viability and signal intensity for MRI detection without compromising further differentiation into definitive cardiac lineages. Labeled hESC-CPCs were transplanted by open surgical methods into the left ventricular free wall of uninjured pig hearts and imaged both ex vivo and in vivo. Comprehensive T 2 *-weighted images were obtained immediately after transplantation and 40 days later before termination. The localization and dispersion of labeled cells could be effectively imaged and tracked at days 0 and 40 by MRI. Thus, under the described conditions, ferumoxytol can be used as a long-term, differentiation-neutral cell-labeling agent to track transplanted hESC-CPCs in vivo using MRI. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:67-74 SIGNIFICANCEThe development of a safe and reproducible in vivo imaging technique to track the fate of transplanted human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs) is a necessary step to clinical translation. An iron oxide nanoparticle (ferumoxytol)-based approach was used for cell labeling and subsequent in vivo magnetic resonance imaging monitoring of hESC-CPCs transplanted into uninjured pig hearts. The present results demonstrate the use of ferumoxytol labeling and imaging techniques in tracking the location and dispersion of cell grafts, highlighting its utility in future cardiac stem cell therapy trials.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Magnetic Resonance Imaging of Iron Oxide-Labeled Human Embryonic Stem Cell-Derived Cardiac Progenitors

Skelton

Khoja

Almeida

et al. 2015

Stem Cells Translational Medicine

View full text Add to dashboard Cite

show abstract

“…As shown in Table V, the vacuolar H 1 -ATPase inhibitor, bafilomycin, as well as ammonia at alkaline pH, suppressed iron uptake, but only partially inhibited iron binding. Under these conditions, bafilomycin did not decrease cellular ATP nor did it inhibit uptake of phosphate (data not shown), indicating that the inhibition is specific to vacuolar ions in different organisms, including plants (Parmley et al, 1978;Kim et al, 2003;Vasconcelos et al, 2003;Arbab et al, 2006;Tallheden et al, 2006) and monitored stained cells by electron microscopy. Bound iron particles were clearly visualized at the extracellullar cell surface (Fig.…”

Section: Bound Iron Is Internalized Into Acidic Vacuolesmentioning

confidence: 92%

Effects of Iron Deficiency on Iron Binding and Internalization into Acidic Vacuoles in Dunaliella salina

et al. 2007

View full text Add to dashboard Cite

Uptake of iron in the halotolerant alga Dunaliella salina is mediated by a transferrin-like protein (TTf), which binds and internalizes Fe 31 ions. Recently, we found that iron deficiency induces a large enhancement of iron binding, which is associated with accumulation of three other plasma membrane proteins that associate with TTf. In this study, we characterized the kinetic properties of iron binding and internalization and identified the site of iron internalization. Iron deficiency induces a 4-fold increase in Fe binding, but only 50% enhancement in the rate of iron uptake and also increases the affinity for iron and bicarbonate, a coligand for iron binding. These results indicate that iron deprivation leads to accumulation and modification of iron-binding sites. Iron uptake in iron-sufficient cells is preceded by an apparent time lag, resulting from prebound iron, which can be eliminated by unloading iron-binding sites. Iron is tightly bound to surface-exposed sites and hardly exchanges with medium iron. All bound iron is subsequently internalized. Accumulation of iron inhibits further iron binding and internalization. The vacuolar inhibitor bafilomycin inhibits iron uptake and internalization. Internalized iron was localized by electron microscopy within vacuolar structures that were identified as acidic vacuoles. Iron internalization is accompanied by endocytosis of surface proteins into these acidic vacuoles. A novel kinetic mechanism for iron uptake is proposed, which includes two pools of bound/compartmentalized iron separated by a rate-limiting internalization stage. The major parameter that is modulated by iron deficiency is the iron-binding capacity. We propose that excessive iron binding in iron-deficient cells serves as a temporary reservoir for iron that is subsequently internalized. This mechanism is particularly suitable for organisms that are exposed to large fluctuations in iron availability.Iron is an essential element for survival for all living organisms, including photosynthetic organisms that have a special requirement for iron as a cofactor of multiple elements in their electron transport system. Because of its low solubility in aerobic solutions, iron is recognized as a major limiting factor for proliferation of plants and algae. To counterbalance iron limitation, photosynthetic organisms evolved efficient high-affinity iron uptake mechanisms that are induced under iron limitation. Two major mechanisms of iron acquisition studied in plants are based either on reduction of organic ferric iron chelates, via a membrane-associated ferrireductase (strategy I plants), or on release of phytosiderophores that bind ferric ions and introduce them into the cell via a special receptor (strategy II plants; Mori, 1999;Curie and Briat, 2003;

show abstract

“…Reporter gene (3)(4)(5) and superparamagnetic iron oxide (SPIO)-based direct cell labeling approaches (6)(7)(8)(9)(10)(11)(12) have been used to track transplanted cells in the heart. However, the issue of whether the SPIO labels remain with the stem cells or are transferred to the scavenger cells has not been directly investigated because of the lack of a marker for cell survival.…”

mentioning

confidence: 99%

Embryonic Stem Cell Grafting in Normal and Infarcted Myocardium: Serial Assessment with MR Imaging and PET Dual Detection

Qiao¹,

Zhang²,

Zheng³

et al. 2009

Radiology

View full text Add to dashboard Cite

Purpose:To use magnetic resonance (MR) imaging and positron emission tomography (PET) dual detection of cardiacgrafted embryonic stem cells (ESCs) to examine (a) survival and proliferation of ESCs in normal and infarcted myocardium, (b) host macrophage versus grafted ESC contribution to serial MR imaging signal over time, and (c) cardiac function associated with the formation of grafts and whether improvement in cardiac function is related to cardiac differentiation of ESCs. Materials and Methods:All animal procedures were approved by the institutional animal care and use committee. Murine ESCs were stably transfected with a mutant version of herpes simplex virus type 1 thymidine kinase, HSV1-sr39tk, and also were labeled with superparamagnetic iron oxide (SPIO) particles. Cells were injected directly in the border zone of the infarcted heart or in corresponding regions of normal hearts in athymic rats. PET and MR imaging were performed longitudinally for 4 weeks in the same animals. Results:ESCs survived and underwent proliferation in the infarcted and normal hearts, as demonstrated by serial increases in 9-(4-[ 18 F]fluoro-3-hydroxymethylbutyl) guanine PET signals. In parallel, the hypointense areas on MR images at the injection sites decreased over time. Double staining for host macrophages and SPIO particles revealed that the majority of SPIO-containing cells were macrophages at week 4 after injection. Left ventricular ejection fraction increased in the ESC-treated rats but decreased in culture media-treated rats, and border-zone function was preserved in ESC-treated animals; however, cardiac differentiation of ESCs was less than 0.5%. Conclusion:Dual-modality imaging permits complementary information in regard to cell survival and proliferation, graft formation, and effects on cardiac function. RSNA, 2009 Supplemental Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, use the Radiology Reprints form at the end of this article. Coronary heart disease accounts for 36% of all cardiovascular death and is the leading cause of heart failure in the United States (1). Although postinfarction survival rates have been improved, congestive heart failure caused by a large infarction or progressive unfavorable ventricular remodeling remains a major problem (2). Despite that cardiac transplantation is currently the most effective therapy, the disparity between organ demand and supply limits its applicability. A treatment strategy often referred to as "cellular cardiomyoplasty" is an attempt at cardiac repair through local (intramyocardial, intracoronary) or systemic (intravenous) delivery of a variety of cells, including fetal or neonatal cardiomyocytes, cardiac cells derived from adult atrial appendages, skeletal myoblasts, embryonic stem cells (ESCs), or bone marrow-derived mesenchymal and hematopoietic stem cells. The strategy is based on the potential of these cells to differentiate into cardiomyocytes to repopulate the ...

show abstract

In vivo MR imaging of magnetically labeled human embryonic stem cells

Cited by 63 publications

References 28 publications

Magnetic Resonance Imaging of Iron Oxide-Labeled Human Embryonic Stem Cell-Derived Cardiac Progenitors

Magnetic Resonance Imaging of Iron Oxide-Labeled Human Embryonic Stem Cell-Derived Cardiac Progenitors

Effects of Iron Deficiency on Iron Binding and Internalization into Acidic Vacuoles in Dunaliella salina

Embryonic Stem Cell Grafting in Normal and Infarcted Myocardium: Serial Assessment with MR Imaging and PET Dual Detection

Contact Info

Product

Resources

About