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. (April 2017)

• Record Type: Journal Article
• Authors: Emmert, Maximilian Y.; Wolint, Petra; Jakab, Andras; Sheehy, Sean P.; Pasqualini, Francesco S.; Nguyen, Thi Dan Linh; Hilbe, Monika; Seifert, Burkhardt; Weber, Benedikt; Brokopp, Chad E.; Macejovska, Dominika; Caliskan, Etem; von Eckardstein, Arnold; Schwartlander, Ruth; Vogel, Viola; Falk, Volkmar; Parker, Kevin Kit; Gyöngyösi, Mariann; Hoerstrup, Simon P.
• Is Part Of: Biomaterials. Volume 122(2017)
• Page Start: 48
• Page End: 62
• Publication Date: 2017-04
• Subjects: Cardiopoietic stem cell therapy -- Mesenchymal stem cells -- Lineage-specification -- Guided cardiopoiesis -- Post-infarction left-ventricular dysfunction -- Left-ventricular remodeling -- Chronic heart-failure; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2016.11.029
• Languages: English
• ISSNs: 0142-9612

Abstract

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.