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Title: Granulocyte-macrophage colony-stimulating factor gene based therapy for acute limb ischemia in a mouse model
Authors: Sacramento, Chester Bittencourt [UNIFESP]
Cantagalli, Vanessa Dionisio [UNIFESP]
Grings, Mariana [UNIFESP]
Carvalho, Leonardo Pinto [UNIFESP]
Costa Baptista-Silva, Jose Carlos [UNIFESP]
Beutel, Abram [UNIFESP]
Bergamaschi, Cassia Toledo [UNIFESP]
Campos, Ruy Ribeiro [UNIFESP]
Moraes, Jane Zveiter de [UNIFESP]
Takiya, Christina Maeda
Samoto, Vivian Yochiko
Borojevic, Radovan
Silva, Flavia Helena da [UNIFESP]
Nardi, Nance Beyer
Dohmann, Hans Fernando
Silva Junior, Hamilton
Valero, Valderez Bastos [UNIFESP]
Han, Sang Won [UNIFESP]
Universidade Federal de São Paulo (UNIFESP)
Universidade Federal do Rio de Janeiro (UFRJ)
Univ Fed Rio Grande do Sul
Excell Biomed Serv
Keywords: angiogenesis
gene therapy
Issue Date: 1-Apr-2009
Publisher: Wiley-Blackwell
Citation: Journal of Gene Medicine. Chichester: John Wiley & Sons Ltd, v. 11, n. 4, p. 345-353, 2009.
Abstract: Background Granulocyte-colony-stimulating factor (GM-CSF) is a pleiotropic factor for hematopoiesis that stimulates myeloblasts, monoblasts and mobilization of bone marrow stem cells. Therefore, the GM-CSF gene is a potential candidate for vessel formation and tissue remodeling in the treatment of ischemic diseases.Methods A new mouse limb ischemia was established by surgery and gene transfer was performed by injection of 100 mu g of a plasmid carrying GM-CSF. Muscle force and weight, histology, capillary density, circulating stem cells and monocytes were determined after 3-4 weeks.Results More than 60% of nontreated ischemic animals showed gangrene below the heel after 4 weeks, whereas the GM-CSF gene-treated animals showed only darkening of nails or toes. These animals demonstrated a full recovery of the affected muscles in terms of weight, force and muscle fiber structure, but the muscles of nontreated ischemic animals lost approximately 50% weight, 86% force and their regular structure. When the GM-CSF gene was injected into the contralateral limb, only partial loss was observed, demonstrating a distant effect of GM-CSF. the capillary density in the GM-CSF-treated group was 52% higher in relation to the nontreated group. Blood analysis by flow cytometry showed that the GMCSF-treated group had 10-20% higher levels of circulating monocytes and Sca-1(+).Conclusions We conclude that the direct administration of GM-CSF gene in limb ischemia had a strong therapeutic effect because it promoted the recovery of muscle mass, force and structure by mobilizing therapeutic cells and augmenting the number of vessels. Copyright (C) 2009 John Wiley & Sons, Ltd.
ISSN: 1099-498X
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