doi: 10.1161/CIRCULATIONAHA.105.541268
(Circulation. 2006;113:1311-1325.)
© 2006 American Heart Association, Inc.
Molecular Cardiology |
Dose-Dependent Contribution of CD34-Positive Cell Transplantation to Concurrent Vasculogenesis and Cardiomyogenesis for Functional Regenerative Recovery After Myocardial Infarction
From Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe (H.I., A.K., M.I., A.O., S.N., H.N., K.S., M.H., T.M., S.M., T.A.); Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine, Osaka (H.I., T.S., S.S.); and Department of Regenerative Medicine Science, Tokai University School of Medicine, Tokai (T.A.), Japan.
Correspondence to Takayuki Asahara, MD, Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. E-mail Asa777{at}aol.com
Received February 8, 2005; revision received August 2, 2005; accepted September 13, 2005.
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.
Methods and 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 1x103 (low), 1x105 (mid), or 5x105 (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 sm22
), 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.
Key Words: angiogenesis • cell therapy • myocardial infarction • transplantation • vasculogenesis
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