Abstract
BackgroundMesenchymal stem cells derived from adipose tissue (ADSC) are multipotent stem cells, originated from the vascular-stromal compartment of fat tissue. ADSC are used as an alternative cell source for many different cell therapies, however in ischemic cardiovascular diseases the therapeutic benefit was modest. One of the reasons could be the use of autologous aged ADSC, which recently were found to have impaired functions. We therefore analysed the effects of age on age markers and angiogenic properties of ADSC. Hypoxic conditioning was investigated as a form of angiogenic stimulation.MethodsADSC were harvested from young (1-3 month), adult (12 month) and aged (18-24 month) mice and cultured under normoxic (20%) and hypoxic (1%) conditions for 48 h. Differences in proliferation, apoptosis and telomere length were assessed in addition to angiogenic properties of ADSC.ResultsProliferation potential and telomere length were decreased in aged ADSC compared to young ADSC. Frequency of apoptotic cells was higher in aged ADSC. Gene expression of pro-angiogenic factors including vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and hepatic growth factor (HGF) were down-regulated with age, which could be restored by hypoxia. Transforming growth factor (TGF-β) increased in the old ADSC but was reduced by hypoxia.Expression of anti-angiogenic factors including thrombospondin-1 (TBS1) and plasminogen activator inhibitor-1 (PAI-1) did increase in old ADSC, but could be reduced by hypoxic stimulation. Endostatin (ENDS) was the highest in aged ADSC and was also down-regulated by hypoxia. We noted higher gene expression of proteases system factors like urokinase-type plasminogen activator receptor (uPAR), matrix metalloproteinases (MMP2 and MMP9) and PAI-1 in aged ADSC compared to young ADSC, but they decreased in old ADSC. Tube formation on matrigel was higher in the presence of conditioned medium from young ADSC in comparison to aged ADSC.ConclusionsADSC isolated from older animals show changes, including impaired proliferation and angiogenic stimulation. Angiogenic gene expression can be partially be improved by hypoxic preconditioning, however the effect is age-dependent. This supports the hypothesis that autologous ADSC from aged subjects might have an impaired therapeutic potential.
Highlights
Mesenchymal stem cells (MSC) have therapeutic potential in bone marrow transplantation [1,2], tissue engineering [3], and cell therapy [4]
As angiogenesis seems to be an important factor in tissue remodelling in cell therapies we investigated the changes of the angiogenesis-related factor production in aged Adipose-derived stem cells (ADSC)
This expression profile is normal for MSC according to the International Society for Cellular Therapy Statement of minimal criteria for defining MSC [41]
Summary
Mesenchymal stem cells (MSC) have therapeutic potential in bone marrow transplantation [1,2], tissue engineering [3], and cell therapy [4]. Adipose-derived stem cells (ADSC) are relatively easy to obtain from adipose tissue and are more frequent than MSC in bone marrow [5]. They represent a promising source for cell therapy, especially as their isolation is less invasive compared to bone marrow extractions and their expansion in culture is quite easy [6,7]. In some studies it was demonstrated that ADSC could release multiple angiogenic growth factors and cytokines/chemokines This suggest that they may have potential as a useful cell source for therapeutic angiogenesis [19]. Hypoxic conditioning was investigated as a form of angiogenic stimulation
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