TLR2-deficiency of cKit+ bone marrow cells is associated with augmented potency to stimulate angiogenic processes.
Copyright policy )TLR2-deficiency of cKit+ bone marrow cells is associated with augmented potency to stimulate angiogenic processes.
Toll-like receptor 2 (TLR2)-deficiency is associated with the preservation of vascular function and TLR2-deficient (TLR2(-/-)) mice exhibit increased neovascularization following induction of hindlimb ischemia. Hematopoietic stem cells play an important role in ischemia-induced angiogenesis and we now investigated whether the effects observed in TLR2(-/-) mice may be attributed to TLR2 deficiency on bone marrow-derived stem cells.cKit-positive (cKit(+)) bone marrow cells (BMC) were isolated from wild type (WT) and TLR2(-/-) mice employing MACS-bead technology. Co-incubation of TLR2(-/-)cKit(+) BMC with mature endothelial cells (ECs) resulted in increased tube formation of ECs on matrigel, augmented sprouting in a 3D-collagen matrix and increased migratory capacity compared to co-incubation with WT cKit(+) BMC. In an in vivo matrigel plug assay, TLR2(-/-)cKit(+) BMC exhibited enhanced formation of capillary-like networks. In a murine model of hindlimb ischemia, administration of TLR2(-/-) cKit(+) BMC to WT mice augmented capillary density and reperfusion of ischemic M. gastrocnemius muscle tissue to the level of TLR2(-/-) mice. Western Blot analysis revealed comparable expression of CXCR4 on TLR2(-/-)cKit(+) BMC but increased activation of the PI3K downstream signaling molecule protein kinase B (PKB/AKT) compared to WT cKit(+) cells.The absence of TLR2 on cKit(+) BMC is associated with augmented potency to support angiogenic processes in vitro and in vivo. Functional inhibition of TLR2 may therefore provide a novel tool to enhance stem cell function for the treatment of vascular diseases.
- University of Rostock Germany
Mice, Knockout, Endothelial Cells, Neovascularization, Physiologic, Bone Marrow Cells, Coculture Techniques, Capillaries, Hindlimb, Mice, Inbred C57BL, Disease Models, Animal, Mice, Proto-Oncogene Proteins c-kit, Ischemia, Human Umbilical Vein Endothelial Cells, Animals, Humans, Phosphatidylinositol 3-Kinase, Muscle, Skeletal, Proto-Oncogene Proteins c-akt, Cells, Cultured, Bone Marrow Transplantation
Mice, Knockout, Endothelial Cells, Neovascularization, Physiologic, Bone Marrow Cells, Coculture Techniques, Capillaries, Hindlimb, Mice, Inbred C57BL, Disease Models, Animal, Mice, Proto-Oncogene Proteins c-kit, Ischemia, Human Umbilical Vein Endothelial Cells, Animals, Humans, Phosphatidylinositol 3-Kinase, Muscle, Skeletal, Proto-Oncogene Proteins c-akt, Cells, Cultured, Bone Marrow Transplantation
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