Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration.
Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool and mobilizes CD45(+)CD11b(+) proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPA improves the incorporation of CD11b(+) cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b(+) cells and VEGFR-1(+) cells, but not carrier-mobilized cells or CD11b(-) cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb ischemia. Thus, tPA mobilizes CD11b(+) cells from the BM and increases systemic and local (cellular) VEGF-A, which can locally promote angiogenesis during ischemic recovery. tPA might be useful to induce therapeutic revascularization in the growing field of regenerative medicine.
Ohki
Makiko
M
Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Ohki
Yuichi
Y
Ishihara
Makoto
M
Nishida
Chiemi
C
Tashiro
Yoshihiko
Y
Akiyama
Haruyo
H
Komiyama
Hiromitsu
H
Lund
Leif R
LR
Nitta
Atsumi
A
Yamada
Kiyofumi
K
Zhu
Zhenping
Z
Ogawa
Hideoki
H
Yagita
Hideo
H
Okumura
Ko
K
Nakauchi
Hiromitsu
H
Werb
Zena
Z
Heissig
Beate
B
Hattori
Koichi
K
D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D039481:CD11b Antigen / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000494:pharmacology; D022423:Myeloid Cells / Q000187:drug effects* / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D010958:Plasminogen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D018183:Transplantation Chimera; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D039481:CD11b Antigen; D017931:DNA Primers; D050505:Mutant Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D010958:Plasminogen; D040281:Vascular Endothelial Growth Factor Receptor-1; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse