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Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

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2020-03-06

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Beltran-Camacho, Lucia
Jimenez-Palomares, Margarita
Rojas-Torres, Marta
Sanchez-Gomar, Ismael
Rosal-Vela, Antonio
Eslava-Alcon, Sara
Perez-Segura, M. Carmen
Serrano, Ana
Antequera-González, Borja
Alonso-Piñero, Jose Angel

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BioMed Central, Springer Nature
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Background: Critical limb ischemia (CLI) constitutes the most aggressive form of peripheral arterial occlusive disease, characterized by the blockade of arteries supplying blood to the lower extremities, significantly diminishing oxygen and nutrient supply. CLI patients usually undergo amputation of fingers, feet, or extremities, with a high risk of mortality due to associated comorbidities. Circulating angiogenic cells (CACs), also known as early endothelial progenitor cells, constitute promising candidates for cell therapy in CLI due to their assigned vascular regenerative properties. Preclinical and clinical assays with CACs have shown promising results. A better understanding of how these cells participate in vascular regeneration would significantly help to potentiate their role in revascularization. Herein, we analyzed the initial molecular mechanisms triggered by human CACs after being administered to a murine model of CLI, in order to understand how these cells promote angiogenesis within the ischemic tissues. Methods: Balb-c nude mice (n:24) were distributed in four different groups: healthy controls (C, n:4), shams (SH, n:4), and ischemic mice (after femoral ligation) that received either 50 μl physiological serum (SC, n:8) or 5 × 105 human CACs (SE, n:8). Ischemic mice were sacrificed on days 2 and 4 (n:4/group/day), and immunohistochemistry assays and qPCR amplification of Alu-human-specific sequences were carried out for cell detection and vascular density measurements. Additionally, a label-free MS-based quantitative approach was performed to identify protein changes related. Results: Administration of CACs induced in the ischemic tissues an increase in the number of blood vessels as well as the diameter size compared to ischemic, non-treated mice, although the number of CACs decreased within time. The initial protein changes taking place in response to ischemia and more importantly, right after administration of CACs to CLI mice, are shown. Conclusions: Our results indicate that CACs migrate to the injured area; moreover, they trigger protein changes correlated with cell migration, cell death, angiogenesis, and arteriogenesis in the host. These changes indicate that CACs promote from the beginning an increase in the number of vessels as well as the development of an appropriate vascular network.

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Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Cell- and Tissue-Based Therapy
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Ischemia
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Nude
Medical Subject Headings::Phenomena and Processes::Circulatory and Respiratory Physiological Phenomena::Cardiovascular Physiological Phenomena::Cardiovascular Physiological Processes::Neovascularization, Physiologic
Medical Subject Headings::Diseases::Cardiovascular Diseases::Vascular Diseases::Peripheral Vascular Diseases::Peripheral Arterial Disease
Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics::Proteomics
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Growth Substances::Angiogenesis Modulating Agents::Angiogenesis Inducing Agents

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Keywords

Critical limb ischemia, Circulating angiogenic cells, Proteomics, Angiogenesis, Arteriogenesis, Isquemia crónica que amenaza las extremidades, Proteómica, Inductores de la angiogénesis

Citation

Beltran-Camacho L, Jimenez-Palomares M, Rojas-Torres M, Sanchez-Gomar I, Rosal-Vela A, Eslava-Alcon S, et al. Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia. Stem Cell Res Ther. 2020 Mar 6;11(1):106