Granulocyte-macrophage colony-stimulating factor gene based therapy for acute limb ischemia in a mouse model

Granulocyte-macrophage colony-stimulating factor gene based therapy for acute limb ischemia in a mouse model

Author Sacramento, Chester Bittencourt Autor UNIFESP Google Scholar
Cantagalli, Vanessa Dionisio Autor UNIFESP Google Scholar
Grings, Mariana Autor UNIFESP Google Scholar
Carvalho, Leonardo Pinto Autor UNIFESP Google Scholar
Costa Baptista-Silva, Jose Carlos Autor UNIFESP Google Scholar
Beutel, Abram Autor UNIFESP Google Scholar
Bergamaschi, Cassia Toledo Autor UNIFESP Google Scholar
Campos, Ruy Ribeiro Autor UNIFESP Google Scholar
Moraes, Jane Zveiter de Autor UNIFESP Google Scholar
Takiya, Christina Maeda Google Scholar
Samoto, Vivian Yochiko Google Scholar
Borojevic, Radovan Google Scholar
Silva, Flavia Helena da Autor UNIFESP Google Scholar
Nardi, Nance Beyer Google Scholar
Dohmann, Hans Fernando Google Scholar
Silva Junior, Hamilton Google Scholar
Valero, Valderez Bastos Autor UNIFESP Google Scholar
Han, Sang Won Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Universidade Federal do Rio de Janeiro (UFRJ)
Univ Fed Rio Grande do Sul
Excell Biomed Serv
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.
Keywords angiogenesis
gene therapy
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 06/59630-0
Date 2009-04-01
Published in Journal of Gene Medicine. Chichester: John Wiley & Sons Ltd, v. 11, n. 4, p. 345-353, 2009.
ISSN 1099-498X (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 345-353
Access rights Closed access
Type Article
Web of Science ID WOS:000265249800007

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