Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines.
BACKGROUND
Bone marrow implantation (BMI) was shown to enhance angiogenesis in a rat ischemic heart model. This preclinical study using a swine model was designed to test the safety and therapeutic effectiveness of BMI.


RESULTS
BM-derived mononuclear cells (BM-MNCs) were injected into 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. Angiography revealed that there was a marked increase (5.7-fold) in number of visible collateral vessels. Implantation of porcine coronary microvascular endothelial cells (CMECs) did not cause any significant increase in capillary densities. Labeled BM-MNCs were incorporated into approximately 31% of neocapillaries and corresponded to approximately 8.7% 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) did not differ between the BMI, CMEC, and medium-alone implantation groups. BM-MNCs contained 16% of endothelial-lineage cells and expressed basic fibroblast growth factor>>vascular endothelial growth factor>angiopoietin 1 mRNAs, and their cardiac levels were significantly upregulated by BMI. Cardiac interleukin-1beta and tumor necrosis factor-alpha mRNA expression were also induced by BMI but not by CMEC implantation. BM-MNCs were actively differentiated to endothelial cells in vitro and formed network structure with human umbilical vein endothelial cells.


CONCLUSIONS
BMI may constitute a novel safety strategy for achieving optimal therapeutic angiogenesis by the natural ability of the BM cells to secrete potent angiogenic ligands and cytokines as well as to be incorporated into foci of neovascularization.
Kamihata
H
H
Department of Medicine II and Cardiovascular Center, Kansai Medical University, Moriguchi, Osaka, Japan.
Matsubara
H
H
Nishiue
T
T
Fujiyama
S
S
Tsutsumi
Y
Y
Ozono
R
R
Masaki
H
H
Mori
Y
Y
Iba
O
O
Tateishi
E
E
Kosaki
A
A
Shintani
S
S
Murohara
T
T
Imaizumi
T
T
Iwasaka
T
T
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000818:Animals; D015152:Blotting, Northern; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D002460:Cell Line; D003097:Collateral Circulation; D003326:Coronary Circulation; D016228:Endothelial Growth Factors / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005786:Gene Expression Regulation; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D008222:Lymphokines / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013556:Swine, Miniature; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016228:Endothelial Growth Factors; D007375:Interleukin-1; D008222:Lymphokines; D008562:Membrane Glycoproteins; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2