Abstract
Introduction: The potency of mesenchymal stem cells (MSCs) related to their biological effects includes immune modulation and angiogenesis. Recently, some stress conditions were applied to enhance the angiogenic potential of MSCs. This study aimed to assess the effects of conditioned media (CM) collected from adipose-derived stem cells’ (ADSCs’) culture under various stress conditions on angiogenesis in vitro.
 Methods: ADSCs were isolated and expanded according to a published protocol. These cells were treated with some stress conditions including hypoxia, starvation, a combination of hypoxia and starvation, and TNF-alpha treatment. CM from these cultures were collected and used for further experiments. The angiogenic potential of CM was evaluated through stimulation of HUVECs to form vessels in vitro. ELISA was used to measure the VEGF concentrations in CM.
 Results: CM-derived various stress ADSC cultures differently affected angiogenesis of HUVECs. The supernatant from a hypoxic culture of ADSCs contained the highest concentration of VEGF and was higher than normoxic culture. However, in others, VEGF concentrations in CM significantly reduced compared to control. CM from TNF-alpha treatment failed to support the formation of blood vessels from HUVECs, while other conditions could support blood vessel formation in vitro. TNF-alpha dually affected both ADSCs and HUVECs. Furthermore, TNF-alpha could stimulate or suppress the VEGF production in dose-response in ADSCs and cause apoptosis in HUVECs at high concentrations.
 Conclusion: CM from the hypoxic culture of ADSCs contained a high concentration of VEGF, supporting angiogenesis of HUVECs well. This is a simple technique that can be used in translational applications. However, the use of TNF-alpha yielded dual effects on ADSCs and HUVECs. Although the VEGF production was enhanced at a low dose of TNF-alpha, they could induce apoptosis in endothelial cells to cause the failure of angiogenesis.
Highlights
The potency of mesenchymal stem cells (MSCs) related to their biological effects includes immune modulation and angiogenesis
The results revealed that in a normal culture condition (G0, control), Adipose derived stem cell conditioned media (CM) (ADSC) could produce a high concentration of VEGF in the CM; this concentration could be increased in a hypoxia condition (6,116 ± 527.9 pg/mL vs. 10,829 ± 640 pg/mL, respectively, for normoxia vs. hypoxia condition; p
In the conditions of TNF-alpha treatment (G1), starvation (G2), or a combination of hypoxia and starvation (G4), the concentrations of VEGF in CM significantly reduced compared to the control (G0; p < 0.05)
Summary
The potency of mesenchymal stem cells (MSCs) related to their biological effects includes immune modulation and angiogenesis. Some stress conditions were applied to enhance the angiogenic potential of MSCs. This study aimed to assess the effects of conditioned media (CM) collected from adipose-derived stem cells' (ADSCs') culture under various stress conditions on angiogenesis in vitro. Lu et al (2018) proved that CM from adipose-derived stem cells (ADSCs) were more efficient in angiogenesis than MSCs from the umbilical cord and endothelium tissues 13 in both in vitro and in vivo conditions. This characteristic depends on the higher levels of many cytokines, and MMPs produced in ADSCs than others, including VEGF, bFGF, PDGF-BB, IGNgamma, IL-10, chemerin, MMP-9, and MMP-13 13. To improve the angiogenic effects of CM from MSC culture, there have been some recent efforts to treat MSCs in some stress conditions or gene modification 14–19. Ogisu et al (2020) cultured MSCs from
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