title: Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report.
abstract: OBJECTIVE
  Comparative studies suggest that stem cells committed to a cardiac lineage are more effective for improving heart function than those featuring an extra-cardiac phenotype. We have therefore developed a population of human embryonic stem cell (ESC)-derived cardiac progenitor cells.
  
  
  RESULTS
  Undifferentiated human ESCs (I6 line) were amplified and cardiac-committed by exposure to bone morphogenetic protein-2 and a fibroblast growth factor receptor inhibitor. Cells responding to these cardio-instructive cues express the cardiac transcription factor Isl-1 and the stage-specific embryonic antigen SSEA-1 which was then used to purify them by immunomagnetic sorting. The Isl-1(+) SSEA-1(+) cells were then embedded into a fibrin scaffold which was surgically delivered onto the infarct area in a 68-year-old patient suffering from severe heart failure [New York Heart Association [NYHA] functional Class III; left ventricular ejection fraction (LVEF): 26%]. A coronary artery bypass was performed concomitantly in a non-infarcted area. The implanted cells featured a high degree of purity (99% were SSEA-1(+)), had lost the expression of Sox-2 and Nanog, taken as markers for pluripotency, and strongly expressed Isl-1. The intraoperative delivery of the patch was expeditious. The post-operative course was uncomplicated either. After 3 months, the patient is symptomatically improved (NYHA functional Class I; LVEF: 36%) and a new-onset contractility is echocardiographically evident in the previously akinetic cell/patch-treated, non-revascularized area. There have been no complications such as arrhythmias, tumour formation, or immunosuppression-related adverse events.
  
  
  CONCLUSIONS
  This observation demonstrates the feasibility of generating a clinical-grade population of human ESC-derived cardiac progenitors and combining it within a tissue-engineered construct. While any conclusion pertaining to efficacy would be meaningless, the patient's functional outcome yet provides an encouraging hint. Beyond this case, the platform that has been set could be useful for generating different ESC-derived lineage-specific progenies.
authors.affiliation: Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20, rue Leblanc, Paris 75015, France University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France INSERM U970, Hôpital Européen Georges Pompidou, Paris, France philippe.menasche@egp.aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Menasché
authors.affiliation: Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris F-75010, France INSERM, CIC de Biothérapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris 75010, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanneaux
authors.affiliation: 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.
authors.forename: Albert
authors.initials: A
authors.lastname: Hagège
authors.affiliation: Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20, rue Leblanc, Paris 75015, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bel
authors.affiliation: University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France Department of Anesthesiology and Intensive Care, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Cholley
authors.affiliation: Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris F-75010, France INSERM, CIC de Biothérapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris 75010, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cacciapuoti
authors.affiliation: Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris F-75010, France INSERM, CIC de Biothérapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris 75010, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Parouchev
authors.affiliation: Department of Biological Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Benhamouda
authors.affiliation: Assistance Publique-Hôpitaux de Paris, University Paris Sud, Histology-Embryology-Cytogenetics, Hôpitaux Universitaires Paris Sud, Clamart 92141, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Tachdjian
authors.affiliation: Assistance Publique-Hôpitaux de Paris, University Paris Sud, Histology-Embryology-Cytogenetics, Hôpitaux Universitaires Paris Sud, Clamart 92141, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Tosca
authors.affiliation: University Paris Descartes, School of Pharmacy, Paris, France Pharmaceutical Innovation Department, Assistance Publique-Hôpitaux de Paris, Central Pharmacy, Paris, France.
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Trouvin
authors.affiliation: Clinical Trials Department, Assistance Publique-Hôpitaux de Paris, Central Pharmacy, Paris, France.
authors.forename: Jean-Roch
authors.initials: JR
authors.lastname: Fabreguettes
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bellamy
authors.affiliation: Department of Biological Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Guillemain
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Laboratoire Régional d'Histocompatibilité Jean Dausset, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Suberbielle Boissel
authors.affiliation: University Paris Descartes, Sorbonne Paris Cité, Paris F-75475, France INSERM U970, Hôpital Européen Georges Pompidou, Paris, France Department of Biological Immunology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Tartour
authors.affiliation: 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Desnos
authors.affiliation: Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris F-75010, France INSERM, CIC de Biothérapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris 75010, France University Paris Diderot, Sorbonne Paris Cité, Paris F-75475, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
mesh_terms: D005260:Female; D006333:Heart Failure / Q000628:therapy*; D000066449:Human Embryonic Stem Cells / Q000637:transplantation*; D006801:Humans; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000628:therapy; D054457:Tissue Scaffolds; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000628:therapy
keywords: Cell therapy; Embryonic stem cells; Heart failure