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1.
Biomedicines ; 9(9)2021 Sep 03.
Article in English | MEDLINE | ID: mdl-34572333

ABSTRACT

Critical limb ischemia (CLI), the most severe form of peripheral artery disease, results from the blockade of peripheral vessels, usually correlated to atherosclerosis. Currently, endovascular and surgical revascularization strategies cannot be applied to all patients due to related comorbidities, and even so, most patients require re-intervention or amputation within a year. Circulating angiogenic cells (CACs) constitute a good alternative as CLI cell therapy due to their vascular regenerative potential, although the mechanisms of action of these cells, as well as their response to pathological conditions, remain unclear. Previously, we have shown that CACs enhance angiogenesis/arteriogenesis from the first days of administration in CLI mice. Also, the incubation ex vivo of these cells with factors secreted by atherosclerotic plaques promotes their activation and mobilization. Herein, we have evaluated the long-term effect of CACs administration in CLI mice, whether pre-stimulated or not with atherosclerotic factors. Remarkably, mice receiving CACs and moreover, pre-stimulated CACs, presented the highest blood flow recovery, lower progression of ischemic symptoms, and decrease of immune cells recruitment. In addition, many proteins potentially involved, like CD44 or matrix metalloproteinase 9 (MMP9), up-regulated in response to ischemia and decreased after CACs administration, were identified by a quantitative proteomics approach. Overall, our data suggest that pre-stimulation of CACs with atherosclerotic factors might potentiate the regenerative properties of these cells in vivo.

2.
Int J Mol Sci ; 21(15)2020 Jul 24.
Article in English | MEDLINE | ID: mdl-32722151

ABSTRACT

In atherosclerosis, circulating angiogenic cells (CAC), also known as early endothelial progenitor cells (eEPC), are thought to participate mainly in a paracrine fashion by promoting the recruitment of other cell populations such as late EPC, or endothelial colony-forming cells (ECFC), to the injured areas. There, ECFC replace the damaged endothelium, promoting neovascularization. However, despite their regenerative role, the number and function of EPC are severely affected under pathological conditions, being essential to further understand how these cells react to such environments in order to implement their use in regenerative cell therapies. Herein, we evaluated the effect of direct incubation ex vivo of healthy CAC with the secretome of atherosclerotic arteries. By using a quantitative proteomics approach, 194 altered proteins were identified in the secretome of pre-conditioned CAC, many of them related to inhibition of angiogenesis (e.g., endostatin, thrombospondin-1, fibulins) and cell migration. Functional assays corroborated that healthy CAC released factors enhanced ECFC angiogenesis, but, after atherosclerotic pre-conditioning, the secretome of pre-stimulated CAC negatively affected ECFC migration, as well as their ability to form tubules on a basement membrane matrix assay. Overall, we have shown here, for the first time, the effect of atherosclerotic factors over the paracrine role of CAC ex vivo. The increased release of angiogenic inhibitors by CAC in response to atherosclerotic factors induced an angiogenic switch, by blocking ECFC ability to form tubules in response to pre-conditioned CAC. Thus, we confirmed here that the angiogenic role of CAC is highly affected by the atherosclerotic environment.


Subject(s)
Atherosclerosis/metabolism , Cell Movement , Cell Proliferation , Endothelial Progenitor Cells/metabolism , Neovascularization, Physiologic , Paracrine Communication , Signal Transduction , Atherosclerosis/pathology , Endothelial Progenitor Cells/pathology , Humans
3.
Stem Cell Res Ther ; 11(1): 106, 2020 03 06.
Article in English | MEDLINE | ID: mdl-32143690

ABSTRACT

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.


Subject(s)
Neovascularization, Physiologic , Peripheral Arterial Disease , Animals , Cell- and Tissue-Based Therapy , Humans , Ischemia/therapy , Mice , Mice, Nude , Peripheral Arterial Disease/therapy
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