Dose-dependent contribution of CD34-positive cell transplantation to concurrent vasculogenesis and cardiomyogenesis for functional regenerative recovery after myocardial infarction.
BACKGROUND
Multilineage developmental capacity of the CD34+ cells, especially into cardiomyocytes and smooth muscle cells (SMCs), is still controversial. In the present study we performed a series of experiments to prove our hypothesis that vasculogenesis and cardiomyogenesis after myocardial infarction (MI) may be dose-dependently enhanced after CD34+ cell transplantation.


RESULTS
Peripheral blood CD34+ cells were isolated from total mononuclear cells of patients with limb ischemia by apheresis after 5-day administration of granulocyte colony-stimulating factor. PBS and 1x10(3) (low), 1x10(5) (mid), or 5x10(5) (high) CD34+ cells were intramyocardially transplanted after ligation of the left anterior descending coronary artery of nude rats. Functional assessments with the use of echocardiography and a microtip conductance catheter at day 28 revealed dose-dependent preservation of left ventricular function by CD34+ cell transplantation. Necropsy examination disclosed dose-dependent augmentation of capillary density and dose-dependent inhibition of left ventricular fibrosis. Immunohistochemistry for human-specific brain natriuretic peptide demonstrated that human cardiomyocytes were dose-dependently observed in ischemic myocardium at day 28 (high, 2480+/-149; mid, 1860+/-141; low, 423+/-9; PBS, 0+/-0/mm2; P<0.05 for high versus mid and mid versus low). Immunostaining for smooth muscle actin and human leukocyte antigen or Ulex europaeus lectin type 1 also revealed dose-dependent vasculogenesis by endothelial cell and SMC development after CD34+ cell transplantation. Reverse transcriptase-polymerase chain reaction indicated that human-specific gene expression of cardiomyocyte (brain natriuretic peptide, cardiac troponin-I, myosin heavy chain, and Nkx 2.5), SMC (smooth muscle actin and sm22alpha), and endothelial cell (CD31 and KDR) markers were dose-dependently augmented in MI tissue.


CONCLUSIONS
Human CD34+ cell transplantation may have significant and dose-dependent potential for vasculogenesis and cardiomyogenesis with functional recovery from MI.
Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan.
Hiroto
H
Iwasaki
Atsuhiko
A
Kawamoto
Masakazu
M
Ishikawa
Akira
A
Oyamada
Shuko
S
Nakamori
Hiromi
H
Nishimura
Kazuyo
K
Sadamoto
Miki
M
Horii
Tomoyuki
T
Matsumoto
Satoshi
S
Murasawa
Toshihiko
T
Shibata
Shigefumi
S
Suehiro
Takayuki
T
Asahara
D000818:Animals; D018952:Antigens, CD34; D002452:Cell Count; D004562:Electrocardiography; D042783:Endothelial Cells / Q000166:cytology; D005355:Fibrosis / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D024510:Muscle Development; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D017202:Myocardial Ischemia / Q000473:pathology; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D018919:Neovascularization, Physiologic; D051381:Rats; D011923:Rats, Nude; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D016277:Ventricular Function, Left
D018952:Antigens, CD34