Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases.
BACKGROUND
Two types of cells are cultured from the human peripheral blood, early endothelial progenitor cells (EPCs) and outgrowth endothelial cells (OECs), as previously reported. Here, we further characterize these cells, especially with respect to their different origins and functions both in vitro and in vivo. We also investigated whether the combination of these different cell types shows synergism during neovascularization.


RESULTS
Early EPCs were heterogeneously made up of both CD14+ monocyte-derived cells, which secrete cytokines, and CD14(-)-derived cells, which contain high levels of (CD34+)KDR+ cells. OECs were cultured almost exclusively from CD14- cells, not CD14+ cells, and were distinct from mature endothelial cells in terms of proliferation potential, KDR+ expression level, and telomerase activity. A portion of cells from CD14- cells and early EPCs produced rapidly proliferating, capillary-forming cells in both the Matrigel plug and the ischemic hind limb similar to OECs. Early EPCs and OECs expressed receptors for vascular endothelial growth factor and interleukin-8, cytokines secreted by early EPCs. There was a differential increase in matrix metalloproteinases (MMPs): MMP-9 in early EPCs and MMP-2 in OECs. In vitro, the angiogenic capability of the 2 cell types was augmented by mutual interaction through cytokines and MMPs. Injection of a mixture of the 2 cells resulted in superior neovascularization in vivo to any single-cell-type transplantation.


CONCLUSIONS
Distinct origins of the different types of EPCs exist that have different functions in neovascularization. Mixed transplantation of these cells results in synergistic neovascularization through cytokines and MMPs.
Yoon
Chang-Hwan
CH
Cardiovascular Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.
Hur
Jin
J
Park
Kyung-Woo
KW
Kim
Ji-Hyun
JH
Lee
Choon-Soo
CS
Oh
Il-Young
IY
Kim
Tae-Youn
TY
Cho
Hyun-Jai
HJ
Kang
Hyun-Jae
HJ
Chae
In-Ho
IH
Yang
Han-Kwang
HK
Oh
Byung-Hee
BH
Park
Young-Bae
YB
Kim
Hyo-Soo
HS
D000818:Animals; D019898:Autocrine Communication; D001773:Blood Cells / Q000166:cytology; D019070:Cell Lineage; D002478:Cells, Cultured; D016922:Cellular Senescence; D016207:Cytokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism / Q000637:transplantation*; D005260:Female; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007511:Ischemia / Q000503:physiopathology / Q000601:surgery*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016207:Cytokines; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases