Ex vivo expanded hematopoietic progenitor cells improve cardiac function after myocardial infarction: role of beta-catenin transduction and cell dose.
Cell-based therapy after myocardial infarction (MI) is a promising therapeutic option but the relevant cell subsets and dosage requirements are poorly defined. We hypothesized that cell therapy for myocardial infarction is improved by ex vivo expansion and high-dose transplantation of defined hematopoietic progenitor cells (HPCs). Since beta-catenin promotes self-renewal of stem cells we evaluated the therapeutic efficacy of beta-catenin-mediated ex vivo expansion of mouse HPCs in a mouse model of myocardial ischemia/reperfusion followed by intraarterial cell delivery. The impact of cell dose was determined by comparing a low-dose (LD, 5 x 10(5) cells) vs. a high-dose (HD, 1 x 10(7) cells) cell transplantation regimen of beta-catenin-HPCs. The impact of beta-catenin modification of HPCs was determined by comparing control-transduced HPCs (GFP-HPCs) vs. transgenic beta-catenin-HPCs. HD beta-catenin-HPCs significantly improved LV function and end-systolic and end-diastolic dimensions as compared to saline and LD beta-catenin-HPCs. Furthermore, while treatment with HD GFP-HPC resulted in a modest cardiac improvement the application of beta-catenin-HPCs was superior, resulting in a significant improvement in EF, FS and LVESD over saline and control GFP-HPC treatment. Although myocardial engraftment of HPCs was only transient, as determined by cell quantification after dye labeling, beta-catenin-HPC treatment significantly decreased infarct size, reduced cardiomyocyte apoptosis and increased capillary angiogenesis in vitro and in vivo. Ex vivo expanded HPCs improve cardiac function and remodeling post MI in a cell number- and beta-catenin-dependent manner.
Templin
Christian
C
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. christian.templin@usz.ch
Kotlarz
Daniel
D
Faulhaber
Jörg
J
Schnabel
Sabine
S
Grote
Karsten
K
Salguero
Gustavo
G
Luchtefeld
Maren
M
Hiller
Karl-Heinz
KH
Jakob
Peter
P
Naim
Hassan Y
HY
Schieffer
Bernhard
B
Hilfiker-Kleiner
Denise
D
Landmesser
Ulf
U
Limbourg
Florian P
FP
Drexler
Helmut
H
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006321:Heart / Q000503:physiopathology*; D006334:Heart Function Tests; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007958:Leukocyte Count; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic; D020257:Ventricular Remodeling / Q000502:physiology; D051176:beta Catenin / Q000235:genetics* / Q000502:physiology
C495270:CTNNB1 protein, human; D051176:beta Catenin