H. Kamihata et al., Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines, CIRCULATION, 104(9), 2001, pp. 1046-1052
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-Bone marrow implantation (BMT) was shown to enhance angiogenesis
in a rat ischemic heart modal. This preclinical study using a swine model
was designed to test the safety and therapeutic effectiveness of BMI.
Methods and Results-BM-derived mononuclear cells (BM-MNCs) were injected in
to a zone, made ischemic by coronary artery ligation. Three weeks after BMI
, regional blood flow and capillary densities were significantly higher (4.
6- and 2.8-fold, respectively), and cardiac function was improved. Angiogra
phy revealed that there was a marked increase (5.7-fold) in number of visib
le collateral vessels. Implantation of porcine coronary microvascular endot
helial cells (CMECs) did not cause any significant increase in capillary de
nsities. Labeled BM-MNCs were incorporated into approximate to 31% of neoca
pillaries and corresponded to approximate to8.7% of macrophages but did not
actively survive as myoblasts or fibroblasts. There was no bone formation
by osteoblasts or malignant ventricular arrhythmia. Time-dependent changes
in plasma levels for cardiac enzymes (troponin I and creatine kinase-MB) di
d not differ between the BMI, CMEC, and medium-alone implantation groups. B
M-MNCs contained 16% of endothelial-lineage calls and expressed basic fibro
blast growth factor much greater than vascular endothelial growth factor>an
giopoiatin 1 mRNAs, and their cardiac levels were significantly upregulated
by BMI. Cardiac interleukin-1 beta and tumor necrosis factor-alpha mRNA ex
pression were also induced by BMI but not by CMEC implantation. BM-MNCs wer
e actively differentiated to endothelial cells in vitro and formed network
structure with human umbilical vein endothelial calls.
Conclusions-BMI may constitute a novel safety strategy for achieving optima
l therapeutic angiogenesis by the natural ability of the BM cells to secret
e potent angiogenic ligands and cytokines as well as to be incorporated int
o foci of neovascularization.