Valérie Bellamy1, Valérie Vanneaux2, Alain Bel3, Hany Nemetalla4, Solène Emmanuelle Boitard5, Yohan Farouz1, Pierre Joanne5, Marie-Cécile Perier1, Estelle Robidel1, Chantal Mandet1, Albert Hagège4, Patrick Bruneval6, Jérôme Larghero2, Onnik Agbulut5, Philippe Menasché7. 1. INSERM U970, Hôpital Européen Georges Pompidou, Paris, France. 2. Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Cell Therapy Unit and Clinical Investigation Center in Biotherapies (CBT501), INSERM UMR1160, Université Sorbonne Paris Cité, Paris, France. 3. INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, Université Sorbonne Paris Cité, Paris, France. 4. INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, Université Sorbonne Paris Cité, Paris, France. 5. Sorbonne Universités, UPMC Univ Paris 06, IBPS, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France. 6. INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Pathology, Université Sorbonne Paris Cité, Paris, France. 7. INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, Université Sorbonne Paris Cité, Paris, France. Electronic address: philippe.menasche@egp.aphp.fr.
Abstract
BACKGROUND: Cardiac-committed cells and biomimetic scaffolds independently improve the therapeutic efficacy of stem cells. In this study we tested the long-term effects of their combination. METHODS: Eighty immune-deficient rats underwent permanent coronary artery ligation. Five to 7 weeks later, those with an echocardiographically measured ejection fraction (EF) ≤55% were re-operated on and randomly allocated to receive a cell-free fibrin patch (n = 25), a fibrin patch loaded with 700,000 human embryonic stem cells (ESC) pre-treated to promote early cardiac differentiation (SSEA-1(+) progenitors [n = 30]), or to serve as sham-operated animals (n = 25). Left ventricular function was assessed by echocardiography at baseline and every month thereafter until 4 months. Hearts were then processed for assessment of fibrosis and angiogenesis and a 5-component heart failure score was constructed by integrating the absolute change in left ventricular end-systolic volume (LVESV) between 4 months and baseline, and the quantitative polymerase chain reaction (qPCR)-based expression of natriuretic peptides A and B, myosin heavy chain 7 and periostin. All data were recorded and analyzed in a blinded manner. RESULTS: The cell-treated group consistently yielded better functional outcomes than the sham-operated group (p = 0.002 for EF; p = 0.01 for LVESV). Angiogenesis in the border zone was also significantly greater in the cell-fibrin group (p = 0.006), which yielded the lowest heart failure score (p = 0.04 vs sham). Engrafted progenitors were only detected shortly after transplantation; no grafted cells were identified after 4 months. There was no teratoma identified. CONCLUSIONS: A fibrin scaffold loaded with ESC-derived cardiac progenitors resulted in sustained improvement in contractility and attenuation of remodeling without sustained donor cell engraftment. A paracrine effect, possibly on innate reparative responses, is a possible mechanism for this enduring effect.
BACKGROUND: Cardiac-committed cells and biomimetic scaffolds independently improve the therapeutic efficacy of stem cells. In this study we tested the long-term effects of their combination. METHODS: Eighty immune-deficient rats underwent permanent coronary artery ligation. Five to 7 weeks later, those with an echocardiographically measured ejection fraction (EF) ≤55% were re-operated on and randomly allocated to receive a cell-free fibrin patch (n = 25), a fibrin patch loaded with 700,000 human embryonic stem cells (ESC) pre-treated to promote early cardiac differentiation (SSEA-1(+) progenitors [n = 30]), or to serve as sham-operated animals (n = 25). Left ventricular function was assessed by echocardiography at baseline and every month thereafter until 4 months. Hearts were then processed for assessment of fibrosis and angiogenesis and a 5-component heart failure score was constructed by integrating the absolute change in left ventricular end-systolic volume (LVESV) between 4 months and baseline, and the quantitative polymerase chain reaction (qPCR)-based expression of natriuretic peptides A and B, myosin heavy chain 7 and periostin. All data were recorded and analyzed in a blinded manner. RESULTS: The cell-treated group consistently yielded better functional outcomes than the sham-operated group (p = 0.002 for EF; p = 0.01 for LVESV). Angiogenesis in the border zone was also significantly greater in the cell-fibrin group (p = 0.006), which yielded the lowest heart failure score (p = 0.04 vs sham). Engrafted progenitors were only detected shortly after transplantation; no grafted cells were identified after 4 months. There was no teratoma identified. CONCLUSIONS: A fibrin scaffold loaded with ESC-derived cardiac progenitors resulted in sustained improvement in contractility and attenuation of remodeling without sustained donor cell engraftment. A paracrine effect, possibly on innate reparative responses, is a possible mechanism for this enduring effect.
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Authors: Sebastian V Rojas; Andreas Martens; Robert Zweigerdt; Hassina Baraki; Christian Rathert; Natalie Schecker; Sara Rojas-Hernandez; Kristin Schwanke; Ulrich Martin; Axel Haverich; Ingo Kutschka Journal: Tissue Eng Part A Date: 2015-07 Impact factor: 3.845