title: Magnetic Resonance Imaging of Iron Oxide-Labeled Human Embryonic Stem Cell-Derived Cardiac Progenitors.
abstract: 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 μg/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 T2*-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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
authors.forename: Rhys J P
authors.initials: RJ
authors.lastname: Skelton
authors.affiliation: Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
authors.forename: Suhail
authors.initials: S
authors.lastname: Khoja
authors.affiliation: Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Shone
authors.initials: S
authors.lastname: Almeida
authors.affiliation: Division of Radiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Rapacchi
authors.affiliation: Division of Radiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.affiliation: Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
authors.forename: James
authors.initials: J
authors.lastname: Engel
authors.affiliation: Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Division of Radiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Hu
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Edouard G
authors.initials: EG
authors.lastname: Stanley
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Elefanty
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Kwon
authors.affiliation: Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia RArdehali@mednet.ucla.edu david.elliott@mcri.edu.au.
authors.forename: David A
authors.initials: DA
authors.lastname: Elliott
authors.affiliation: Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA RArdehali@mednet.ucla.edu david.elliott@mcri.edu.au.
authors.forename: Reza
authors.initials: R
authors.lastname: Ardehali
mesh_terms: D058948:Cell Tracking / Q000379:methods*; D053595:Embryonic Stem Cells / Q000000981:diagnostic imaging / Q000637:transplantation; D005290:Ferric Compounds / Q000494:pharmacology; D052203:Ferrosoferric Oxide / Q000493:pharmacokinetics / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D008279:Magnetic Resonance Imaging; D032386:Myoblasts, Cardiac / Q000000981:diagnostic imaging / Q000637:transplantation; D011859:Radiography; D033581:Stem Cell Transplantation
chemical_list: D005290:Ferric Compounds; C000499:ferric oxide; D052203:Ferrosoferric Oxide
keywords: Cardiac stem cell biology; Cardiovascular progenitors; Cell labeling; Magnetic resonance imaging; Stem cell therapy