title: Transplantation and tracking of human-induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment, and distribution by hybrid single photon emission computed tomography/computed tomography of sodium iodide symporter transgene expression.
abstract: BACKGROUND
  Evaluation of novel cellular therapies in large-animal models and patients is currently hampered by the lack of imaging approaches that allow for long-term monitoring of viable transplanted cells. In this study, sodium iodide symporter (NIS) transgene imaging was evaluated as an approach to follow in vivo survival, engraftment, and distribution of human-induced pluripotent stem cell (hiPSC) derivatives in a pig model of myocardial infarction.
  
  
  RESULTS
  Transgenic hiPSC lines stably expressing a fluorescent reporter and NIS (NIS(pos)-hiPSCs) were established. Iodide uptake, efflux, and viability of NIS(pos)-hiPSCs were assessed in vitro. Ten (±2) days after induction of myocardial infarction by transient occlusion of the left anterior descending artery, catheter-based intramyocardial injection of NIS(pos)-hiPSCs guided by 3-dimensional NOGA mapping was performed. Dual-isotope single photon emission computed tomographic/computed tomographic imaging was applied with the use of (123)I to follow donor cell survival and distribution and with the use of (99m)TC-tetrofosmin for perfusion imaging. In vitro, iodide uptake in NIS(pos)-hiPSCs was increased 100-fold above that of nontransgenic controls. In vivo, viable NIS(pos)-hiPSCs could be visualized for up to 15 weeks. Immunohistochemistry demonstrated that hiPSC-derived endothelial cells contributed to vascularization. Up to 12 to 15 weeks after transplantation, no teratomas were detected.
  
  
  CONCLUSIONS
  This study describes for the first time the feasibility of repeated long-term in vivo imaging of viability and tissue distribution of cellular grafts in large animals. Moreover, this is the first report demonstrating vascular differentiation and long-term engraftment of hiPSCs in a large-animal model of myocardial infarction. NIS(pos)-hiPSCs represent a valuable tool to monitor and improve current cellular treatment strategies in clinically relevant animal models.
authors: Department of Cardiology, University Hospital Zurich, Rämistrasse 100, 8091 Zürich, Switzerland. Christian.Templin@usz.ch
authors: Christian
authors: C
authors: Templin
authors: Robert
authors: R
authors: Zweigerdt
authors: Kristin
authors: K
authors: Schwanke
authors: Ruth
authors: R
authors: Olmer
authors: Jelena-Rima
authors: JR
authors: Ghadri
authors: Maximilian Y
authors: MY
authors: Emmert
authors: Ennio
authors: E
authors: Müller
authors: Silke M
authors: SM
authors: Küest
authors: Susan
authors: S
authors: Cohrs
authors: Roger
authors: R
authors: Schibli
authors: Peter
authors: P
authors: Kronen
authors: Monika
authors: M
authors: Hilbe
authors: Andreas
authors: A
authors: Reinisch
authors: Dirk
authors: D
authors: Strunk
authors: Axel
authors: A
authors: Haverich
authors: Simon
authors: S
authors: Hoerstrup
authors: Thomas F
authors: TF
authors: Lüscher
authors: Philipp A
authors: PA
authors: Kaufmann
authors: Ulf
authors: U
authors: Landmesser
authors: Ulrich
authors: U
authors: Martin
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D004195:Disease Models, Animal; D005240:Feasibility Studies; D015870:Gene Expression; D006085:Graft Survival; D006321:Heart / Q000000981:diagnostic imaging; D006801:Humans; D066298:In Vitro Techniques; D007267:Injections; D064847:Multimodal Imaging; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D039904:Pluripotent Stem Cells / Q000378:metabolism* / Q000637:transplantation*; D049268:Positron-Emission Tomography; D033581:Stem Cell Transplantation / Q000379:methods; D013552:Swine; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D019076:Transgenes; D016896:Treatment Outcome; D000099209:Sodium-Iodide Symporters
chemical_list: D027981:Symporters; D000099209:Sodium-Iodide Symporters