Specific Jagged-1 signal from bone marrow microenvironment is required for endothelial progenitor cell development for neovascularization.
BACKGROUND
Despite accumulating evidence that proves the pivotal role of endothelial progenitor cells (EPCs) in ischemic neovascularization, the key signaling cascade that regulates functional EPC kinetics remains unclear.


RESULTS
In this report, we show that inactivation of specific Jagged-1 (Jag-1)-mediated Notch signals leads to inhibition of postnatal vasculogenesis in hindlimb ischemia via impairment of proliferation, survival, differentiation, and mobilization of bone marrow-derived EPCs. Bone marrow-derived EPCs obtained from Jag-1-/- mice, but not Delta-like (Dll)-1-/- mice, demonstrated less therapeutic potential for ischemic neovascularization than EPCs from the wild type. In contrast, a gain-of-function study using 3T3 stromal cells overexpressing Notch ligand revealed that Jag-1-mediated Notch signals promoted EPC commitment, which resulted in enhanced neovascularization. The impaired neovascularization in Jag-1-/- mice was profoundly rescued by transplantation of Jag-1-stimulated EPCs.


CONCLUSIONS
These data indicate that specific Jag-1-derived Notch signals from the bone marrow microenvironment are critical for EPC-mediated vasculogenesis, thus providing an important clue for modulation of strategies for therapeutic neovascularization.
Kwon
Sang-Mo
SM
Stem Cell Translational Research Laboratory, RIKEN Center For Developmental Biology/Institute of Biomedical Research and Innovation, Kobe, Japan.
Eguchi
Masamichi
M
Wada
Mika
M
Iwami
Yo
Y
Hozumi
Katsuhito
K
Iwaguro
Hideki
H
Masuda
Haruchika
H
Kawamoto
Atsuhiko
A
Asahara
Takayuki
T
D000818:Animals; D001853:Bone Marrow / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000502:physiology*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins