Pivotal role of lnk adaptor protein in endothelial progenitor cell biology for vascular regeneration.

Abstract

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.

• Authors: 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
• Journal: Circulation research (Circ Res) Vol. 104 Issue 8 Pg. 969-77 (Apr 24 2009) ISSN: 1524-4571 [Electronic] United States
• PMID: 19325148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antigens, CD34
• Cytokines
• Intracellular Signaling Peptides and Proteins
• Lnk protein, mouse
• Membrane Proteins
• Proteins
• Stem Cell Factor
• Proto-Oncogene Proteins c-kit

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Antigens, CD34 (metabolism)
• Astrocytes (metabolism)
• Bone Marrow Cells (metabolism)
• Bone Marrow Transplantation
• Cell Lineage
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Cytokines (metabolism)
• Disease Models, Animal
• Endothelial Cells (metabolism, transplantation)
• Hindlimb
• Intracellular Signaling Peptides and Proteins
• Ischemia (metabolism, physiopathology, surgery)
• Membrane Proteins
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Nude
• Muscle, Skeletal (blood supply)
• Neovascularization, Physiologic
• Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-kit (metabolism)
• Regeneration
• Retinal Neovascularization (metabolism, physiopathology)
• Signal Transduction
• Stem Cell Factor (metabolism)
• Stem Cells (metabolism)
• Time Factors