title: Safety and efficacy of cardiopoietic stem cells in the treatment of post-infarction left-ventricular dysfunction - From cardioprotection to functional repair in a translational pig infarction model.
abstract: To date, clinical success of cardiac cell-therapies remains limited. To enhance the cardioreparative properties of stem cells, the concept of lineage-specification through cardiopoietic-guidance has been recently suggested. However, so far, only results from murine studies and from a clinical pilot-trial in chronic heart-failure (CHF) are available, while systematic evidence of its therapeutic-efficacy is still lacking. Importantly, also no data from large animals or for other indications are available. Therefore, we here investigate the therapeutic-efficacy of human cardiopoietic stem cells in the treatment of post-infarction LV-dysfunction using a translational pig-model. Using growth-factor priming, lineage-specification of human bone-marrow derived MSCs was achieved to generate cardiopoietic stem cells according to GMP-compliant protocols. Thereafter, pigs with post-infarction LV-dysfunction (sub-acute phase;1-month) were randomized to either receive transcatheter NOGA 3D electromechanical-mapping guided intramyocardial transplantation of cardiopoietic cells or saline (control). After 30days, cardiac MRI (cMRI) was performed for functional evaluation and in-vivo cell-tracking. This approach was coupled with a comprehensive post-mortem cell-fate and mode-of-repair analysis. Cardiopoietic cell therapy was safe and ejection-fraction was significantly higher when compared to controls (p = 0.012). It further prevented maladaptive LV-remodeling and revealed a significantly lower relative and total infarct-size (p = 0.043 and p = 0.012). As in-vivo tracking and post-mortem analysis displayed only limited intramyocardial cardiopoietic cell-integration, the significant induction of neo-angiogenesis (∼40% higher; p = 0.003) and recruitment of endogenous progenitors (∼2.5x higher; p = 0.008) to the infarct border-zone appeared to be the major modes-of-repair. This is the first report using a pre-clinical large animal-model to demonstrate the safety and efficacy of cardiopoietic stem cells for the treatment of post-infarction LV-dysfunction to prevent negative LV-remodeling and subsequent CHF. It further provides insight into post-delivery cardiopoietic cell-fate and suggests the mechanisms of cardiopoietic cell-induced cardiac-repair. The adoption of GMP-/GLP-compliant methodologies may accelerate the translation into a phase-I clinical-trial in patients with post-ischemic LV-dysfunction broadening the current indication of this interesting cell-type.
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland; Clinic for Cardiac Surgery, University Hospital of Zurich, Zurich, Switzerland; Wyss Translational Center Zurich, ETH and University of Zurich, Zurich, Switzerland; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, USA. Electronic address: maximilian.emmert@usz.ch.
authors.forename: Maximilian Y
authors.initials: MY
authors.lastname: Emmert
authors.affiliation: Clinic for Cardiac Surgery, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Wolint
authors.affiliation: Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria.
authors.forename: Andras
authors.initials: A
authors.lastname: Jakab
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Sheehy
authors.affiliation: Wyss Translational Center Zurich, ETH and University of Zurich, Zurich, Switzerland; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, USA.
authors.forename: Francesco S
authors.initials: FS
authors.lastname: Pasqualini
authors.affiliation: Institute of Diagnostic Radiology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Thi Dan Linh
authors.initials: TDL
authors.lastname: Nguyen
authors.affiliation: Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Hilbe
authors.affiliation: Department of Biostatistics; Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland.
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Seifert
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, USA.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Weber
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Brokopp
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Dominika
authors.initials: D
authors.lastname: Macejovska
authors.affiliation: Clinic for Cardiac Surgery, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Etem
authors.initials: E
authors.lastname: Caliskan
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
authors.affiliation: Department of Health Science and Technology, Laboratory of Applied Mechanobiology, ETH Zurich, Zurich, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Schwartlander
authors.affiliation: Department of Health Science and Technology, Laboratory of Applied Mechanobiology, ETH Zurich, Zurich, Switzerland.
authors.forename: Viola
authors.initials: V
authors.lastname: Vogel
authors.affiliation: Clinic for Cardiac Surgery, German Heart Center Berlin, Berlin, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Falk
authors.affiliation: Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, USA.
authors.forename: Kevin Kit
authors.initials: KK
authors.lastname: Parker
authors.affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors.forename: Mariann
authors.initials: M
authors.lastname: Gyöngyösi
authors.affiliation: Institute for Regenerative Medicine (IREM), University of Zurich, Zurich, Switzerland; Wyss Translational Center Zurich, ETH and University of Zurich, Zurich, Switzerland; Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, USA.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hoerstrup
mesh_terms: D000818:Animals; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology* / Q000628:therapy*; D020127:Recovery of Function; D013552:Swine; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy*; D020257:Ventricular Remodeling
keywords: Cardiopoietic stem cell therapy; Chronic heart-failure; Guided cardiopoiesis; Left-ventricular remodeling; Lineage-specification; Mesenchymal stem cells; Post-infarction left-ventricular dysfunction