Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience
Authors: Lucie Tosca
Yohan Farouz
Alain Bel
Jean-Roch Fabreguettes
Jean-Hugues Trouvin
Patrick Bruneval
Odile Damour
Albert Hagège
Onnik Agbulut
Valérie Bellamy
Marie-Cécile Périer
Gérard Tachdjian
Michel Desnos
Jérôme Larghero
Julia Pouly
Philippe Menasché
Valérie Vanneaux
Sylvie Garcia
Journal: European Heart Journal (2015)
Discipline: CLINICAL MEDICINE
Keywords: Cell therapy; Heart failure; Myocardial infarction; Stem cells; Tissue engineering.
Affiliations: Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France, University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France, INSERM U970, Hôpital Européen Georges Pompidou, Paris, France, Cell Therapy Unit and Clinical Investigation Center in Biotherapies (CBT501), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris F-75475, France, INSERM UMRS1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France, Central Pharmacy, Clinical Trials Department, Assistance Publique-Hôpitaux de Paris, Paris, France, Assistance Publique-Hôpitaux de Paris, University Paris Sud, Histology-Embryology-Cytogenetics, Hôpitaux Universitaires Paris Sud, Clamart 92141, France, Unité de Biologie des Populations Lymphocytaires, Department of Immunology, Institut Pasteur, CNRS-URA 1961, Paris, France, Tissues and Cells Bank, Edouard Herriot Hospital, Lyon, France, Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France, Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France, Department of Pathology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France, School of Pharmacy, University Paris Descartes, Paris, France, Central Pharmacy, Pharmaceutical Innovation Department, Assistance Publique-Hôpitaux de Paris, Paris, France

Abstract:  Aim: There is now compelling evidence that cells committed to a cardiac lineage are most effective for improving the function of infarcted hearts. This has been confirmed by our pre-clinical studies entailing transplantation of human embryonic stem cell (hESC)-derived cardiac progenitors in rat and non-human primate models of myocardial infarction. These data have paved the way for a translational programme aimed at a phase I clinical trial. Methods and results: The main steps of this programme have included (i) the expansion of a clone of pluripotent hESC to generate a master cell bank under good manufacturing practice conditions (GMP); (ii) a growth factor-induced cardiac specification; (iii) the purification of committed cells by immunomagnetic sorting to yield a stage-specific embryonic antigen (SSEA)-1-positive cell population strongly expressing the early cardiac transcription factor Isl-1; (iv) the incorporation of these cells into a fibrin scaffold; (v) a safety assessment focused on the loss of teratoma-forming cells by in vitro (transcriptomics) and in vivo (cell injections in immunodeficient mice) measurements; (vi) an extensive cytogenetic and viral testing; and (vii) the characterization of the final cell product and its release criteria. The data collected throughout this process have led to approval by the French regulatory authorities for a first-in-man clinical trial of transplantation of these SSEA-1(+) progenitors in patients with severely impaired cardiac function. Conclusion: Although several facets of this manufacturing process still need to be improved, these data may yet provide a useful platform for the production of hESC-derived cardiac progenitor cells under safe and cost-effective GMP conditions. 

Retracted: No

PubPeer comments:
 This publication includes many wrong statements and serious flaws. A few examples:  Conversely, the BMP-2-committed progenitors up-regulated genes that mark cardiac progenitor cells (predominantly Isl-1, but also GATA6, HAND1, EOMES) as well as more developmentally advanced cardiomyocytes (MYLK7, MYLK 9, tropomyosin1, MYH9, HAPLN1). Comment: EOMES and ISL1 are expressed at very different stages of development. They cannot be concommitantly expressed . MYH9 in a non-muscle myosin . HAPLN1 is an ubiquitous gene encoding an extracellular matrix protein Figure 2A: the legend does not fit with the data illustrated by the heatmap Figure 2B: the heatmap reveals genes not expected to be expressed in any cardiac lineage : some examples: GATA2, GATA3, neuronal genes such as NEDD9, ISL1 also in motoneurons, in pancreas.., HPGD....in fact a vast majority of the genes expressed in the cell population are not cardiac . One should conclude that the sorted cell population is composed of many cell types but cardiac progenitor or cardiac cells A serious point: This heatmap has been cut at the bottom One could not find the transcriptomic data in Geodataset or in arryexpress . ,