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(Circulation. 2008;118:157-165.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Specific Jagged-1 Signal From Bone Marrow Microenvironment Is Required for Endothelial Progenitor Cell Development for Neovascularization

Sang-Mo Kwon, PhD; Masamichi Eguchi, MD; Mika Wada, MD, PhD; Yo Iwami, MD, PhD; Katsuhito Hozumi, PhD; Hideki Iwaguro, MD, PhD; Haruchika Masuda, MD, PhD; Atsuhiko Kawamoto, MD, PhD; Takayuki Asahara, MD, PhD

From the Stem Cell Translational Research Laboratory (S.-M.K., H.I., H.M., A.K., T.A.), RIKEN Center For Developmental Biology/Institute of Biomedical Research and Innovation, Kobe, Japan; and Department of Regenerative Medicine Science (S.-M.K., M.E., M.W., Y.I., H.I., H.M., T.A.) and Department of Immunology (K.H.), Center for Embryogenesis and Organogenesis, Tokai University School of Medicine, Isehara, Japan.

Correspondence to Takayuki Asahara, MD, PhD, Department of Regenerative Medicine Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan 259-1193. E-mail asa777{at}is.icc.u-tokai.ac.jp

Received November 25, 2007; accepted April 18, 2008.

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.

Methods and 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 105-106. [Extract] [Full Text]