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

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• 作者：Maximilian Y. Emmert^a ; ^b ; ^c ; ^d ; ^{maximilian.emmert@usz.ch} ; Petra Wolint^b ; Andras Jakab^e ; Sean P. Sheehy^d ; Francesco S. Pasqualini^c ; ^d ; Thi Dan Linh Nguyen^f ; Monika Hilbe^g ; Burkhardt Seifert^h ; Benedikt Weber^a ; ^d ; Chad E. Brokopp^a ; Dominika Macejovskaⁱ ; Etem Caliskan^b ; Arnold von Eckardstein^j ; Ruth Schwartlander^k ; Viola Vogel^k ; Volkmar Falk^l ; Kevin Kit Parker^d ; Mariann Gyö ; ngyö ; siⁱ ; Simon P. Hoerstrup^a ; ^c ; ^d
• 关键词：Cardiopoietic stem cell therapy ; Mesenchymal stem cells ; Lineage-specification ; Guided cardiopoiesis ; Post-infarction left-ventricular dysfunction ; Left-ventricular remodeling ; Chronic heart-failure
• 刊名：Biomaterials
• 出版年：2017
• 出版时间：April 2017
• 年：2017
• 卷：122
• 期：Complete
• 页码：48-62
• 全文大小：5715 K
• 卷排序：122

文摘

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.