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Eur Heart J. 2015 Mar 21;36(12):743-50. doi: 10.1093/eurheartj/ehu192. Epub 2014 May 16.

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

Author information

1
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.
2
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.
3
Central Pharmacy, Clinical Trials Department, Assistance Publique-Hôpitaux de Paris, Paris, France.
4
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.
5
Assistance Publique-Hôpitaux de Paris, University Paris Sud, Histology-Embryology-Cytogenetics, Hôpitaux Universitaires Paris Sud, Clamart 92141, France.
6
Unité de Biologie des Populations Lymphocytaires, Department of Immunology, Institut Pasteur, CNRS-URA 1961, Paris, France.
7
INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
8
University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
9
Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France.
10
Tissues and Cells Bank, Edouard Herriot Hospital, Lyon, France.
11
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.
12
Sorbonne Universités, UPMC Univ Paris 06, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France.
13
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.
14
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.

KEYWORDS:

Cell therapy; Heart failure; Myocardial infarction; Stem cells; Tissue engineering

PMID:
24835485
DOI:
10.1093/eurheartj/ehu192
[Indexed for MEDLINE]

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