Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization.
The discovery of bone marrow-derived endothelial progenitors in the peripheral blood has promoted intensive studies on the potential of cell therapy for various human diseases. Accumulating evidence has suggested that implantation of bone marrow mononuclear cells effectively promotes neovascularization in ischemic tissues. It has also been reported that the implanted cells are incorporated not only into the newly formed vessels but also secrete angiogenic factors. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. We enrolled 29 "no-option" patients with critical limb ischemia and treated ischemic limbs by implantation of peripheral mononuclear cells. Cell therapy using peripheral mononuclear cells was very effective for the treatment of limb ischemia, and its efficacy was associated with increases in the plasma levels of angiogenic factors, in particular interleukin-1beta (IL-1beta). We then examined an experimental model of limb ischemia using IL-1beta-deficient mice. Implantation of IL-1beta-deficient mononuclear cells improved tissue ischemia as efficiently as that of wild-type cells. Both wild-type and IL-1beta-deficient mononuclear cells increased expression of IL-1beta and thus induced angiogenic factors in muscle cells of ischemic limbs to a similar extent. In contrast, inability of muscle cells to secrete IL-1beta markedly reduces induction of angiogenic factors and impairs neovascularization by cell implantation. Implanted cells do not secret angiogenic factors sufficient for neovascularization but, instead, stimulate muscle cells to produce angiogenic factors, thereby promoting neovascularization in ischemic tissues. Further studies will allow us to develop more effective treatments for ischemic vascular disease.
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan.
Kaoru
K
Tateno
Tohru
T
Minamino
Haruhiro
H
Toko
Hiroshi
H
Akazawa
Naomi
N
Shimizu
Shinichi
S
Takeda
Takeshige
T
Kunieda
Hideyuki
H
Miyauchi
Tomomi
T
Oyama
Katsuhisa
K
Matsuura
Jun-ichiro
J
Nishi
Yoshio
Y
Kobayashi
Toshio
T
Nagai
Yoichi
Y
Kuwabara
Yoichiro
Y
Iwakura
Fumio
F
Nomura
Yasushi
Y
Saito
Issei
I
Komuro
D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005121:Extremities / Q000098:blood supply*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000097:blood / Q000172:deficiency; D007511:Ischemia / Q000097:blood / Q000503:physiopathology / Q000601:surgery*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000637:transplantation*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D018919:Neovascularization, Physiologic
D043925:Angiogenesis Inducing Agents; D007375:Interleukin-1