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(Circulation Research. 2009;104:969.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Pivotal Role of Lnk Adaptor Protein in Endothelial Progenitor Cell Biology for Vascular Regeneration

Sang-Mo Kwon^*, Takahiro Suzuki^*, Atsuhiko Kawamoto, Masaaki Ii, Masamichi Eguchi, Hiroshi Akimaru, Mika Wada, Tomoyuki Matsumoto, Haruchika Masuda, Yoshihiro Nakagawa, Hiromi Nishimura, Kenji Kawai, Satoshi Takaki, Takayuki Asahara

From the Departments of Regenerative Medicine Science (S.-M.K., M.E., M.W., H.M., K.K., T.A.) and Ophthalmology (T.S., Y.N.), Tokai University School of Medicine, Isehara; Vascular Regeneration Research Group (S.-M.K., A.K., M.I., H.A., T.M., H.N., T.A.), Institute of Biomedical Research and Innovation, Kobe; and Department of Community Health and Medicine (S.T.), Research Institute, International Medical Center of Japan, Tokyo.

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

Despite the fact that endothelial progenitor cells (EPCs) are important for postnatal neovascularization, their origins, differentiation, and modulators are not clear. Here, we demonstrate that Lnk, a negative regulator of hematopoietic stem cell proliferation, controls endothelial commitment of c-kit⁺/Sca-1⁺/Lineage^– (KSL) subpopulations of bone marrow cells. The results of EPC colony–forming assays reveal that small (primitive) EPC colony formation by CD34^– KSLs and large (definitive) EPC colony formation by CD34^(dim) KSLs are more robust in lnk^–/– mice. In hindlimb ischemia, perfusion recovery is augmented in lnk^–/– mice through enhanced proliferation and mobilization of EPCs via c-Kit/stem cell factor. We found that Lnk-deficient EPCs are more potent actors than resident cells in hindlimb perfusion recovery and ischemic neovascularization, mainly via the activity of bone marrow-EPCs. Similarly, lnk^–/– mice show augmented retinal neovascularization and astrocyte network maturation without an increase in indicators of pathogenic angiogenesis in an in vivo model of retinopathy. Taken together, our results provide strong evidence that Lnk regulates bone marrow-EPC kinetics in vascular regeneration. Selective targeting of Lnk may be a safe and effective strategy to augment therapeutic neovascularization by EPC transplantation.

Key Words: endothelial progenitor cell • lnk • vascular regeneration