Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia

Jae Choon Ryu, Brian P. Davidson, Aris Xie, Qi Yue, Daogang Zha, J. Todd Belcik, Evan S. Caplan, Juliana M. Woda, Catherine C. Hedrick, Richard N. Hanna, Nicholas Lehman, Yan Zhao, Anthony Ting, Jonathan Lindner

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    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. 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 CX3CR-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. (Circulation. 2013;127:710-719.).

    Original languageEnglish (US)
    Pages (from-to)710-719
    Number of pages10
    JournalCirculation
    Volume127
    Issue number6
    DOIs
    StatePublished - Feb 12 2013

    Fingerprint

    Molecular Imaging
    Cell- and Tissue-Based Therapy
    Stem Cells
    Ischemia
    Extremities
    Monocytes
    Ligation
    Leukocyte Rolling
    Abdominal Muscles
    Selectins
    P-Selectin
    Iliac Artery
    Optical Imaging
    Chemotaxis
    Conditioned Culture Medium
    Blood Volume
    Luciferases
    Ultrasonography
    Tumor Necrosis Factor-alpha

    Keywords

    • Angiogenesis
    • Echocardiography
    • Molecular imaging
    • Peripheral arterial disease
    • Stem cells

    ASJC Scopus subject areas

    • Physiology (medical)
    • Cardiology and Cardiovascular Medicine

    Cite this

    Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia. / Ryu, Jae Choon; Davidson, Brian P.; Xie, Aris; Yue, Qi; Zha, Daogang; Belcik, J. Todd; Caplan, Evan S.; Woda, Juliana M.; Hedrick, Catherine C.; Hanna, Richard N.; Lehman, Nicholas; Zhao, Yan; Ting, Anthony; Lindner, Jonathan.

    In: Circulation, Vol. 127, No. 6, 12.02.2013, p. 710-719.

    Research output: Contribution to journalArticle

    Ryu, JC, Davidson, BP, Xie, A, Yue, Q, Zha, D, Belcik, JT, Caplan, ES, Woda, JM, Hedrick, CC, Hanna, RN, Lehman, N, Zhao, Y, Ting, A & Lindner, J 2013, 'Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia', Circulation, vol. 127, no. 6, pp. 710-719. https://doi.org/10.1161/CIRCULATIONAHA.112.116103
    Ryu, Jae Choon ; Davidson, Brian P. ; Xie, Aris ; Yue, Qi ; Zha, Daogang ; Belcik, J. Todd ; Caplan, Evan S. ; Woda, Juliana M. ; Hedrick, Catherine C. ; Hanna, Richard N. ; Lehman, Nicholas ; Zhao, Yan ; Ting, Anthony ; Lindner, Jonathan. / Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia. In: Circulation. 2013 ; Vol. 127, No. 6. pp. 710-719.
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    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. 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 CX3CR-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. (Circulation. 2013;127:710-719.).",
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    AU - Davidson, Brian P.

    AU - Xie, Aris

    AU - Yue, Qi

    AU - Zha, Daogang

    AU - Belcik, J. Todd

    AU - Caplan, Evan S.

    AU - Woda, Juliana M.

    AU - Hedrick, Catherine C.

    AU - Hanna, Richard N.

    AU - Lehman, Nicholas

    AU - Zhao, Yan

    AU - Ting, Anthony

    AU - Lindner, Jonathan

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