Journal
EUROPEAN HEART JOURNAL
Volume 36, Issue 12, Pages 743-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehu192
Keywords
Stem cells; Cell therapy; Tissue engineering; Heart failure; Myocardial infarction
Categories
Funding
- Assistance Publique-Hopitaux de Paris
- LabEx REVIVE
- Foundation LeDucq (SHAPE-HEART network)
- Fondation de France
- Fondation Coeur et Arteres
- Association Francaise contre les Myopathies [ANR-10-IBHU-0002]
- Hospices Civils de Lyon
- INSERM
- University Paris Descartes
- Agence Nationale de la Recherche (ANR) [ANR-10-IBHU-0002] Funding Source: Agence Nationale de la Recherche (ANR)
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Aim This paper describes the multi-step translational approach that has resulted in the generation of clinical-grade human embryonic stem cell-derived cardiac progenitor cells for transplantation in patients with severe ischaemic heart failure. 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.
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