Document Detail


Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia.
MedLine Citation:
PMID:  23307829     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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:
Jae Choon Ryu; Brian P Davidson; Aris Xie; Yue Qi; Daogang Zha; J Todd Belcik; Evan S Caplan; Juliana M Woda; Catherine C Hedrick; Richard N Hanna; Nicholas Lehman; Yan Zhao; Anthony Ting; Jonathan R Lindner
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-10
Journal Detail:
Title:  Circulation     Volume:  127     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-12     Completed Date:  2013-04-10     Revised Date:  2014-02-13    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  710-9     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adult Stem Cells / drug effects,  transplantation,  ultrasonography
Animals
Antigens, CD14 / analysis
Cell Movement / physiology
Extremities / blood supply*,  pathology,  ultrasonography
Humans
Iliac Artery / drug effects,  physiopathology,  ultrasonography
Ischemia / pathology,  therapy*,  ultrasonography
Mice
Mice, Inbred C57BL
Microvessels / drug effects,  pathology,  physiopathology,  ultrasonography
Molecular Imaging*
Monocytes / pathology,  physiology
Multipotent Stem Cells / drug effects,  transplantation,  ultrasonography
Muscle, Skeletal / blood supply,  pathology,  ultrasonography
Neovascularization, Physiologic / drug effects,  physiology*
P-Selectin / biosynthesis
Paracrine Communication / drug effects,  physiology*
Receptors, Chemokine / analysis
Stem Cell Transplantation*
Transplantation, Heterologous
Tumor Necrosis Factor-alpha / pharmacology
Grant Support
ID/Acronym/Agency:
R01 DK063508/DK/NIDDK NIH HHS; R01 HL074443/HL/NHLBI NIH HHS; R01 HL078610/HL/NHLBI NIH HHS; R01 HL111969/HL/NHLBI NIH HHS; R01-DK-063508/DK/NIDDK NIH HHS; R01-HL-071141/HL/NHLBI NIH HHS; R01-HL-078610/HL/NHLBI NIH HHS; RC1 HL100659/HL/NHLBI NIH HHS; RC1-HL-100659/HL/NHLBI NIH HHS; T32-HL094294/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD14; 0/Cx3cr1 protein, mouse; 0/P-Selectin; 0/Receptors, Chemokine; 0/Tumor Necrosis Factor-alpha
Comments/Corrections

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