Abstract
Senescence reduces the circulating number and angiogenic activity of endothelial progenitor cells (EPCs), and is associated with aging-related vascular diseases. However, it is very time-consuming to obtain aged cells (~1 month of repeated replication) or animals (~2 years) for senescence studies. Here, we established an accelerated senescence model by treating EPCs with deferoxamine (DFO), an FDA-approved iron chelator. Four days of low-dose (3 μM) DFO induced senescent phenotypes in EPCs, including a senescent pattern of protein expression, impaired mitochondrial bioenergetics, altered mitochondrial protein levels and compromised angiogenic activity. DFO-treated early EPCs from young and old donors (< 35 vs. > 70 years old) displayed similar senescent phenotypes, including elevated senescence-associated β-galactosidase activity and reduced relative telomere lengths, colony-forming units and adenosine triphosphate levels. To validate this accelerated senescence model in vivo, we intraperitoneally injected Sprague-Dawley rats with DFO for 4 weeks. Early EPCs from DFO-treated rats displayed profoundly senescent phenotypes compared to those from control rats. Additionally, in hind-limb ischemic mice, DFO pretreatment compromised EPC angiogenesis by reducing both blood perfusion and capillary density. DFO thus accelerates EPC senescence and appears to hasten model development for cellular senescence studies.
Highlights
The therapeutic potential of endothelial progenitor cells (EPCs) for ischemic diseases has attracted great interest since Asahara et al first identified these cells in adult peripheral blood samples in 1997 [1]
Considering that DFO compromised the angiogenic activity of EPCs, we examined whether four-day DFO treatment altered the expression of angiogenic proteins such as vascular endothelial growth factor (VEGF), Fms-related receptor tyrosine kinase 1 (Flt-1), kinase insert domain receptor (KDR) and TEK receptor tyrosine kinase (TIE2) in EPCs (Figure 3C–3F)
Treatment successfully induced EPC senescence in vitro, ex vivo and in vivo, closely mimicking the senescent phenotypes induced by repeated replication or natural aging [14]
Summary
The therapeutic potential of endothelial progenitor cells (EPCs) for ischemic diseases has attracted great interest since Asahara et al first identified these cells in adult peripheral blood samples in 1997 [1]. The number of circulating EPCs is reduced in diabetes mellitus patients, is negatively associated with the Framingham cardiovascular risk score [2], and is positively associated with vascular function [1,2,3]. EPCs are needed for vascular repair, and for the regulation of angiogenesis, and protect organs and tissues from critical ischemia in terminal atherosclerotic diseases [2, 4]. EPCs have been widely used to treat patients with ischemic cardiovascular disease and diabetic foot ischemia [5]. Aging is an independent risk factor for the development of atherosclerosis-related diseases, so EPC senescence may promote atherosclerosis in elderly patients. As progenitor cells are more senescence-resistant than proper somatic cells, timeconsuming procedures are needed to obtain sufficient quantities of senescent EPCs for routine assays. About www.aging-us.com one month of repeated replication is needed to obtain senescent EPCs in vitro, and about two years are needed to obtain them from old rats or mice in vivo
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