Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
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 philippe.menasche@egp.aphp.fr.
Philippe
P
Menasché
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.
Valérie
V
Vanneaux
Central Pharmacy, Clinical Trials Department, Assistance Publique-Hôpitaux de Paris, Paris, France.
Jean-Roch
JR
Fabreguettes
Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
Alain
A
Bel
Assistance Publique-Hôpitaux de Paris, University Paris Sud, Histology-Embryology-Cytogenetics, Hôpitaux Universitaires Paris Sud, Clamart 92141, France.
Lucie
L
Tosca
Unité de Biologie des Populations Lymphocytaires, Department of Immunology, Institut Pasteur, CNRS-URA 1961, Paris, France.
Sylvie
S
Garcia
INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
Valérie
V
Bellamy
University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
Yohan
Y
Farouz
Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France.
Julia
J
Pouly
Tissues and Cells Bank, Edouard Herriot Hospital, Lyon, France.
Odile
O
Damour
INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
Marie-Cécile
MC
Périer
University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France INSERM U970, Hôpital Européen Georges Pompidou, Paris, France Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
Michel
M
Desnos
University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France INSERM U970, Hôpital Européen Georges Pompidou, Paris, France Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
Albert
A
Hagège
Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France.
Onnik
O
Agbulut
University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France INSERM U970, Hôpital Européen Georges Pompidou, Paris, France Department of Pathology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
Patrick
P
Bruneval
Assistance Publique-Hôpitaux de Paris, University Paris Sud, Histology-Embryology-Cytogenetics, Hôpitaux Universitaires Paris Sud, Clamart 92141, France.
Gérard
G
Tachdjian
School of Pharmacy, University Paris Descartes, Paris, France Central Pharmacy, Pharmaceutical Innovation Department, Assistance Publique-Hôpitaux de Paris, Paris, France.
Jean-Hugues
JH
Trouvin
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.
Jérôme
J
Larghero
D000818:Animals; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D017321:Clinical Trials, Phase I as Topic; D020732:Cytogenetic Analysis; D005069:Evaluation Studies as Topic; D000066449:Human Embryonic Stem Cells / Q000637:transplantation*; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods*; D016513:Mice, SCID; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation; D014015:Tissue Banks / Q000458:organization & administration*; D014021:Tissue Preservation / Q000379:methods; D054457:Tissue Scaffolds
Cell therapy; Heart failure; Myocardial infarction; Stem cells; Tissue engineering