Long-term benefit of intracardiac delivery of autologous granulocyte-colony-stimulating factor-mobilized blood CD34+ cells containing cardiac progenitors on regional heart structure and function after myocardial infarct.
OBJECTIVE
Starting from experimental data proposing hematopoietic stem cells as candidates for cardiac repair, we postulated that human peripheral blood (PB) CD34+ cells mobilized by hematopoietic growth-factor (G-CSF) would contain cell subpopulations capable of regenerating post-ischemic myocardial damages.


METHODS
In a phase I clinical assay enrolling seven patients with acute myocardial infarct, we directly delivered to the injured myocardium autologous PB CD34+ cells previously mobilized by G-CSF, collected by leukapheresis and purified by immunoselection. In parallel, we looked for the eventual presence of cardiomyocytic and endothelial progenitor cells in leukapheresis products of these patients and controls, using flow cytometry, reverse transcription-quantitative (RTQ)-polymerase chain reaction (PCR), cell cultures and immunofluorescence analyzes.


RESULTS
The whole clinical process was feasible and safe. All patients were alive at an average follow-up of 49 months (range 24-76 months). Improvement of heart function parameters became obvious from the third month following cell reinjection. Left ventricular ejection fraction values progressively and dramatically increased with time, associated with PetScan demonstration of myocardial structure regeneration and revascularization and New York Heart Association (NYHA) grade improvement. Furthermore, we identified PB CD34+ cell subpopulations expressing characteristics of both immature and mature endothelial and cardiomyocyte progenitor cells. In vitro CD34+ cell cultures on a specific medium induced development of adherent cells featuring morphologies, gene expression and immunocytochemistry characteristics of endothelial and cardiac muscle cells.


CONCLUSIONS
Mobilized CD34+ cells contain stem cells committed along endothelial and cardiac differentiation pathways, which could play a key role in a proposed two-phase mechanism of myocardial regeneration after direct intracardiac delivery, probably being responsible for the long-term clinical benefit observed.
Pasquet
Stéphanie
S
Institut de Recherche en Hématologie et Transplantation (IRHT), Mulhouse, France.
Sovalat
Hanna
H
Hénon
Philippe
P
Bischoff
Nicolas
N
Arkam
Yazid
Y
Ojeda-Uribe
Mario
M
Bouar
Ronan le
Rl
Rimelen
Valérie
V
Brink
Ingo
I
Dallemand
Robert
R
Monassier
Jean-Pierre
JP
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D054337:Cell Dedifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D004333:Drug Administration Routes; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D018952:Antigens, CD34; D009124:Muscle Proteins; D016179:Granulocyte Colony-Stimulating Factor