BACKGROUND: Human cardiac progenitor cells have demonstrated great potential for myocardial repair in small and large animals, but robust methods for longitudinal assessment of their engraftment in humans is not yet readily available. In this study, we sought to optimize and evaluate the use of positron emission tomography (PET) reporter gene imaging for monitoring human cardiac progenitor cell (hCPC) transplantation in a mouse model of myocardial infarction. METHODS AND RESULTS: hCPCs were isolated and expanded from human myocardial samples and stably transduced with herpes simplex virus thymidine kinase (TK) PET reporter gene. Thymidine kinase-expressing hCPCs were characterized in vitro and transplanted into murine myocardial infarction models (n=57). Cardiac echocardiographic, magnetic resonance imaging and pressure-volume loop analyses revealed improvement in left ventricular contractile function 2 weeks after transplant (hCPC versus phosphate-buffered saline, P<0.03). Noninvasive PET imaging was used to track hCPC fate over a 4-week time period, demonstrating a substantial decline in surviving cells. Importantly, early cell engraftment as assessed by PET was found to predict subsequent functional improvement, implying a "dose-effect" relationship. We isolated the transplanted cells from recipient myocardium by laser capture microdissection for in vivo transcriptome analysis. Our results provide direct evidence that hCPCs augment cardiac function after their transplantation into ischemic myocardium through paracrine secretion of growth factors. CONCLUSIONS: PET reporter gene imaging can provide important diagnostic and prognostic information regarding the ultimate success of hCPC treatment for myocardial infarction.
BACKGROUND:Human cardiac progenitor cells have demonstrated great potential for myocardial repair in small and large animals, but robust methods for longitudinal assessment of their engraftment in humans is not yet readily available. In this study, we sought to optimize and evaluate the use of positron emission tomography (PET) reporter gene imaging for monitoring human cardiac progenitor cell (hCPC) transplantation in a mouse model of myocardial infarction. METHODS AND RESULTS: hCPCs were isolated and expanded from human myocardial samples and stably transduced with herpes simplex virus thymidine kinase (TK) PET reporter gene. Thymidine kinase-expressing hCPCs were characterized in vitro and transplanted into murinemyocardial infarction models (n=57). Cardiac echocardiographic, magnetic resonance imaging and pressure-volume loop analyses revealed improvement in left ventricular contractile function 2 weeks after transplant (hCPC versus phosphate-buffered saline, P<0.03). Noninvasive PET imaging was used to track hCPC fate over a 4-week time period, demonstrating a substantial decline in surviving cells. Importantly, early cell engraftment as assessed by PET was found to predict subsequent functional improvement, implying a "dose-effect" relationship. We isolated the transplanted cells from recipient myocardium by laser capture microdissection for in vivo transcriptome analysis. Our results provide direct evidence that hCPCs augment cardiac function after their transplantation into ischemic myocardium through paracrine secretion of growth factors. CONCLUSIONS: PET reporter gene imaging can provide important diagnostic and prognostic information regarding the ultimate success of hCPC treatment for myocardial infarction.
Authors: Jonathan M Hill; Alexander J Dick; Venkatesh K Raman; Richard B Thompson; Zu-Xi Yu; K Allison Hinds; Breno S S Pessanha; Michael A Guttman; Timothy R Varney; Bradley J Martin; Cynthia E Dunbar; Elliot R McVeigh; Robert J Lederman Journal: Circulation Date: 2003-08-11 Impact factor: 29.690
Authors: P van Vliet; M Roccio; A M Smits; A A M van Oorschot; C H G Metz; T A B van Veen; J P G Sluijter; P A Doevendans; M-J Goumans Journal: Neth Heart J Date: 2008-05 Impact factor: 2.380
Authors: Arthur J Moss; Wojciech Zareba; W Jackson Hall; Helmut Klein; David J Wilber; David S Cannom; James P Daubert; Steven L Higgins; Mary W Brown; Mark L Andrews Journal: N Engl J Med Date: 2002-03-19 Impact factor: 91.245
Authors: Jan Balzarini; Sandra Liekens; Nicola Solaroli; Kamel El Omari; David K Stammers; Anna Karlsson Journal: J Biol Chem Date: 2006-05-15 Impact factor: 5.157
Authors: Marie-José Goumans; Teun P de Boer; Anke M Smits; Linda W van Laake; Patrick van Vliet; Corina H G Metz; Tom H Korfage; K Peter Kats; Ron Hochstenbach; Gerard Pasterkamp; Marianne C Verhaar; Marcel A G van der Heyden; Dominique de Kleijn; Christine L Mummery; Toon A B van Veen; Joost P G Sluijter; Pieter A Doevendans Journal: Stem Cell Res Date: 2008-03-12 Impact factor: 2.020
Authors: Michael A Laflamme; Kent Y Chen; Anna V Naumova; Veronica Muskheli; James A Fugate; Sarah K Dupras; Hans Reinecke; Chunhui Xu; Mohammad Hassanipour; Shailaja Police; Chris O'Sullivan; Lila Collins; Yinhong Chen; Elina Minami; Edward A Gill; Shuichi Ueno; Chun Yuan; Joseph Gold; Charles E Murry Journal: Nat Biotechnol Date: 2007-08-26 Impact factor: 54.908
Authors: Anke M Smits; Patrick van Vliet; Corina H Metz; Tom Korfage; Joost Pg Sluijter; Pieter A Doevendans; Marie-José Goumans Journal: Nat Protoc Date: 2009 Impact factor: 13.491
Authors: Peter Vanderslice; Ronald J Biediger; Darren G Woodside; Wells S Brown; Sayadeth Khounlo; Navin D Warier; C William Gundlach; Amy R Caivano; William G Bornmann; David S Maxwell; Bradley W McIntyre; James T Willerson; Richard A F Dixon Journal: J Biol Chem Date: 2013-05-23 Impact factor: 5.157
Authors: Audrey E Mayfield; Everad L Tilokee; Nicholas Latham; Brian McNeill; Bu-Khanh Lam; Marc Ruel; Erik J Suuronen; David W Courtman; Duncan J Stewart; Darryl R Davis Journal: Biomaterials Date: 2013-10-04 Impact factor: 12.479