Serial in vivo positive contrast MRI of iron oxide‐labeled embryonic stem cell‐derived cardiac precursor cells in a mouse model of myocardial infarction

Mani, Venkatesh; Adler, Eric; Briley‐Saebo, Karen C.; Bystrup, Anne; Fuster, Valentín; Keller, Gordon; Fayad, Zahi A.

doi:10.1002/mrm.21642

Cited by 61 publications

(58 citation statements)

References 37 publications

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“…Recently methods of tracking cells, using MRI or optical imaging methods, have been shown to be possible in settings such as heart attacks and stroke [22,62,113]. This holds much promise for evaluating where injected cells end up residing which will be particularly important for assessing the validity of cell-based treatments.…”

Section: How Do We Assess Success?mentioning

confidence: 99%

Tissue engineering and the intervertebral disc: the challenges

2008

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Disc degeneration is a common disorder. Although the back pain that can develop in association with this is rarely life-threatening, the annual cost in terms of morbidity, lost productivity, medical expenses and workers' compensation benefits is significant. Surgical intervention as practised currently is directed towards removing the damaged or altered tissue. Development of new treatment modalities is critical as there is a growing consensus that the strategies used currently for symptomatic degenerative disc disease may not be effective. Accordingly, there is a need to develop an entirely new way to treat this disorder; regenerative medicine and tissue engineering approaches appear particularly promising in this regard. This paper reviews some of the challenges that currently are limiting the clinical application of this approach to the treatment of disc degeneration.

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Section: How Do We Assess Success?mentioning

confidence: 99%

Tissue engineering and the intervertebral disc: the challenges

2008

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“…EMT is observed routinely in developmental processes, but is also believed to play an important role in the migration, invasion, and metastasis of various cancers (6)(7)(8)(9). It also promotes the generation of cancer stem cells, thereby contributing to tumor recurrence and metastasis (10,11). Two recent publications have challenged this dogma for breast and pancreatic cancers and have suggested instead that EMT confers chemoresistance rather than metastatic potential to tumor cells (12,13).…”

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confidence: 99%

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

Kodama

Newberg

Kodama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial-mesenchymal transition (EMT) is thought to contribute to metastasis and chemoresistance in patients with hepatocellular carcinoma (HCC), leading to their poor prognosis. The genes driving EMT in HCC are not yet fully understood, however. Here, we show that mobilization of Sleeping Beauty (SB) transposons in immortalized mouse hepatoblasts induces mesenchymal liver tumors on transplantation to nude mice. These tumors show significant down-regulation of epithelial markers, along with up-regulation of mesenchymal markers and EMT-related transcription factors (EMTTFs). Sequencing of transposon insertion sites from tumors identified 233 candidate cancer genes (CCGs) that were enriched for genes and cellular processes driving EMT. Subsequent trunk driver analysis identified 23 CCGs that are predicted to function early in tumorigenesis and whose mutation or alteration in patients with HCC is correlated with poor patient survival. Validation of the top trunk drivers identified in the screen, including MET (MET proto-oncogene, receptor tyrosine kinase), GRB2-associated binding protein 1 (GAB1), HECT, UBA, and WWE domain containing 1 (HUWE1), lysine-specific demethylase 6A (KDM6A), and protein-tyrosine phosphatase, nonreceptor-type 12 (PTPN12), showed that deregulation of these genes activates an EMT program in human HCC cells that enhances tumor cell migration. Finally, deregulation of these genes in human HCC was found to confer sorafenib resistance through apoptotic tolerance and reduced proliferation, consistent with recent studies showing that EMT contributes to the chemoresistance of tumor cells. Our unique cell-based transposon mutagenesis screen appears to be an excellent resource for discovering genes involved in EMT in human HCC and potentially for identifying new drug targets.H CC is the sixth most common cancer and the third-leading cause of cancer-related deaths worldwide (1). In the United States, the incidence of HCC is increasing, and overall 5-y survival is now <12%, despite recent progress in diagnostic and therapeutic modalities (2). This high mortality rate is related mainly to a high recurrence rate and associated intrahepatic or extrahepatic metastases (1). Patients with HCC who develop metastasis are no longer eligible for liver transplantation therapy and have very limited therapeutic options. Currently, sorafenib is the sole systemic antineoplastic agent for HCC described in the National Comprehensive Cancer Network (NCCN) guideline (3); however, its clinical benefit is limited (4), and alternative effective treatments are needed for these patients.Epithelial-mesenchymal transition (EMT) is a complex differentiation process whereby epithelial cells lose their identity and acquire mesenchymal characteristics (5). EMT is observed routinely in developmental processes, but is also believed to play an important role in the migration, invasion, and metastasis of various cancers (6-9). It also promotes the generation of cancer stem cells, thereby contributing to tumor recurrence and metastasis...

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“…Recent studies, however, have shown that iron oxide labeling, combined with magnetic targeting, might improve graft retention in the rat heart [29,30,34,36]. Thus, ferumoxytol cell labeling might have utility in both in vivo cardiac graft imaging and cell retention.…”

confidence: 99%

“…Recent studies have described the properties of the ultra-small superparamagnetic iron oxide nanoparticle, ferumoxytol (Feraheme; AMAG Pharmaceuticals, Inc., Waltham, MA, http://www.amagpharma.com) as a labeling agent [7,14,[29][30][31]. Ferumoxytol interacts with cells via a synthetic carbohydrate coating and is currently used for the treatment of iron-deficiency anemia in the presence of chronic kidney disease [32].…”

Section: Introductionmentioning

confidence: 99%

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

Skelton

Khoja

Almeida

et al. 2015

Stem Cells Translational Medicine

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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.

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Serial in vivo positive contrast MRI of iron oxide‐labeled embryonic stem cell‐derived cardiac precursor cells in a mouse model of myocardial infarction

Cited by 61 publications

References 37 publications

Tissue engineering and the intervertebral disc: the challenges

Tissue engineering and the intervertebral disc: the challenges

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

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

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