Bone marrow-derived myocyte-like cells and regulation of repair-related cytokines after bone marrow cell transplantation.
OBJECTIVE
Whether bone marrow cells injected following acute myocardial infarction (MI) transdifferentiate into cardiomyocytes remains controversial, and how these cells affect repair-related cytokines is not known.


METHODS
Autologous bone marrow-derived mononuclear cells (BM-MNCs) labeled with DiI, 1,1'-dioctadecyl-1 to 3,3,3',3'-tetramethylindocarbocyanine perchlorate, or saline were intravenously injected into rabbits 5 h following a 30-min ischemia and reperfusion protocol, and cardiac function and the general pathology of the infarcted heart were followed up 1 and 3 months post-MI. To search for regenerated myocardium, electron microscopy as well as confocal microscopy were performed in the infarcted myocardium 7 days post-MI. Expression levels of repair-related cytokines were evaluated by immunohistochemistry and Western blotting.


RESULTS
Improvements in cardiac function and reductions in infarct size were observed in the BM-MNC group 1 month and 3 months post-MI. Using electron microscopy 7 days after infarction, clusters of very immature (fetal) and relatively mature cardiomyocytes undergoing differentiation were identified in the infarcted anterior LV wall in the BM-MNC group, though their numbers were small. These cells contained many small and dense DiI particles (a BM-MNC marker), indicating that cardiomyocytes had regenerated from the injected BM-MNCs. The expression of both transforming growth factor-beta, which stimulates collagen synthesis and matrix metalloproteinase-1, a collagenase, were both down-regulated 7 days and 1 month post-MI in the BM-MNC group. Stromal cell-derived factor-1, which is known to recruit BM-MNCs into target tissues, was overexpressed in the infarcted areas of BM-MNC hearts 7 days post-MI.


CONCLUSIONS
Intravenous transplantation of BM-MNCs leads to the development of BM-MNC-derived myocyte-like cells and regulates the expression of repair-related cytokines that facilitate repair following myocardial infarction.
Misao
Yu
Y
Department of Cardiology, Regeneration Medicine and Bioethics, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Takemura
Genzou
G
Arai
Masazumi
M
Sato
Shigeru
S
Suzuki
Koji
K
Miyata
Shusaku
S
Kosai
Ken-ichiro
K
Minatoguchi
Shinya
S
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000032:analysis; D016207:Cytokines / Q000032:analysis*; D007150:Immunohistochemistry / Q000379:methods; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D017202:Myocardial Ischemia / Q000276:immunology / Q000473:pathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000648:ultrastructure; D011817:Rabbits; D012038:Regeneration; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000032:analysis
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016207:Cytokines; D016212:Transforming Growth Factor beta; D020781:Matrix Metalloproteinase 1