title: Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia.
abstract: BACKGROUND
  Stem cells are thought to enhance vascular remodeling in ischemic tissue in part through paracrine effects. Using molecular imaging, we tested the hypothesis that treatment of limb ischemia with multipotential adult progenitor cells (MAPCs) promotes recovery of blood flow through the recruitment of proangiogenic monocytes.
  
  
  RESULTS
  Hind-limb ischemia was produced in mice by iliac artery ligation, and MAPCs were administered intramuscularly on day 1. Optical imaging of luciferase-transfected MAPCs indicated that cells survived for 1 week. Contrast-enhanced ultrasound on days 3, 7, and 21 showed a more complete recovery of blood flow and greater expansion of microvascular blood volume in MAPC-treated mice than in controls. Fluorescent microangiography demonstrated more complete distribution of flow to microvascular units in MAPC-treated mice. On ultrasound molecular imaging, expression of endothelial P-selectin and intravascular recruitment of CX(3)CR-1-positive monocytes were significantly higher in MAPC-treated mice than in the control groups at days 3 and 7 after arterial ligation. Muscle immunohistology showed a >10-fold-greater infiltration of monocytes in MAPC-treated than control-treated ischemic limbs at all time points. Intravital microscopy of ischemic or tumor necrosis factor-α-treated cremaster muscle demonstrated that MAPCs migrate to perimicrovascular locations and potentiate selectin-dependent leukocyte rolling. In vitro migration of human CD14(+) monocytes was 10-fold greater in response to MAPC-conditioned than basal media.
  
  
  CONCLUSIONS
  In limb ischemia, MAPCs stimulate the recruitment of proangiogenic monocytes through endothelial activation and enhanced chemotaxis. These responses are sustained beyond the MAPC lifespan, suggesting that paracrine effects promote flow recovery by rebalancing the immune response toward a more regenerative phenotype.
authors: Division of Cardiovascular Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Jae Choon
authors: JC
authors: Ryu
authors: Brian P
authors: BP
authors: Davidson
authors: Aris
authors: A
authors: Xie
authors: Yue
authors: Y
authors: Qi
authors: Daogang
authors: D
authors: Zha
authors: J Todd
authors: JT
authors: Belcik
authors: Evan S
authors: ES
authors: Caplan
authors: Juliana M
authors: JM
authors: Woda
authors: Catherine C
authors: CC
authors: Hedrick
authors: Richard N
authors: RN
authors: Hanna
authors: Nicholas
authors: N
authors: Lehman
authors: Yan
authors: Y
authors: Zhao
authors: Anthony
authors: A
authors: Ting
authors: Jonathan R
authors: JR
authors: Lindner
mesh_terms: D053687:Adult Stem Cells / Q000000981:diagnostic imaging / Q000187:drug effects / Q000637:transplantation; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000502:physiology; D005121:Extremities / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D007083:Iliac Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D007511:Ischemia / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D057054:Molecular Imaging; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D039902:Multipotent Stem Cells / Q000000981:diagnostic imaging / Q000187:drug effects / Q000637:transplantation; D018482:Muscle, Skeletal / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D019007:P-Selectin / Q000096:biosynthesis; D019899:Paracrine Communication / Q000187:drug effects / Q000502:physiology*; D019707:Receptors, Chemokine / Q000032:analysis; D033581:Stem Cell Transplantation; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014463:Ultrasonography
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D018950:Lipopolysaccharide Receptors; D019007:P-Selectin; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha