Systemic levels of G-CSF and interleukin-6 determine the angiogenic potential of bone marrow resident monocytes.
There is considerable interest in the potential of cell-based approaches to mediate therapeutic angiogenesis for acute and chronic vascular syndromes. Using a mouse model of HLI, we showed previously that adoptive transfer of a small number of donor monocytes enhanced revascularization significantly. Herein, we provide data suggesting that the BM resident monocytes sense systemic signals that influence their future functional capacity. Specifically, following induction of distant ischemia, the angiogenic capacity of BM resident monocytes is reduced markedly. We provide evidence that G-CSF and IL-6 represent such "conditioning" signals. Systemic levels of G-CSF and IL-6 are increased significantly following induction of HLI. Accordingly, BM resident monocytes from ischemic mice exhibited increased pSTAT3 and STAT3 target gene expression. Finally, G-CSFR(-/-) and IL-6(-/-) mice were resistant to the deleterious effects of ischemic conditioning on monocyte angiogenic potential. RNA expression profiling suggested that ischemia-conditioned monocytes in the BM up-regulate the well-described M2 polarization markers Chi3l4 and Lrg1. Consistent with this observation, M2-skewed monocytes from SHIP(-/-) mice also had impaired angiogenic capacity. Collectively, these data show that G-CSF and IL-6 provide signals that determine the angiogenic potential of BM resident monocytes.
Gregory
Alyssa D
AD
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Capoccia
Benjamin J
BJ
Woloszynek
Jill R
JR
Link
Daniel C
DC
D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply; D015850:Interleukin-6 / Q000502:physiology*; D007511:Ischemia; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D018919:Neovascularization, Physiologic; D050796:STAT3 Transcription Factor / Q000378:metabolism
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor