Activated Endothelium Stimulates the Activity of Multipotent Mesenchymal Stromal Cells under Physiological Hypoxia or Short-Term Hypoxic Stress in vitro

Multipotent mesenchymal stromal cells (MSCs) are used forsupplementary therapy of ischemic and inflammatory diseases. Aftersystemic administration, transmigration of MSCs to target tissuesis accompanied by their interaction with activated endothelial cells(ECs) at the site of injury. In this study, we investigated theeffects of TNF-α-activated ECs on MSC functions under differentlevels of hypoxia. For this purpose, the short-term direct co-cultureof MSCs and activated TNF-α endothelial cells was used. MSCs retainedtheir stromal phenotype and multilineage differentiation potentialafter the interaction with activated ECs. At the same time, therewere detected changes in the expression of molecules involved inMSC contacts with other cells and the extracellular matrix (ECM),as well as in regulating ECM degradation and cell migration. Furthermore,conditioned medium from activated endothelium stimulated targetedand untargeted migration of MSCs. The interaction of MSCs with activatedECs enhanced the paracrine activity of both cell types due to upregulatedtranscription and elevated levels of pleiotropic cytokines IL-6and IL-8, and altered the protease–antiprotease balance. These datasuggest that short-term interaction of MSCs with activated ECs mayplay an important role in tissue reparative and remodeling processes.Specifically, it may promote the migratory phenotype of MSCs. Incontrast to physiological hypoxia (5% O₂),acute hypoxic stress (0.1% O₂, 24 h) attenuatedthe stimulatory effects of ECs on MSCs.