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

Abstract

Multipotent mesenchymal stromal cells (MSCs) are used for supplementary therapy of ischemic and inflammatory diseases. After systemic administration, transmigration of MSCs to target tissues is accompanied by their interaction with activated endothelial cells (ECs) at the site of injury. In this study, we investigated the effects of TNF-α-activated ECs on MSC functions under different levels of hypoxia. For this purpose, the short-term direct co-culture of MSCs and activated TNF-α endothelial cells was used. MSCs retained their stromal phenotype and multilineage differentiation potential after the interaction with activated ECs. At the same time, there were detected changes in the expression of molecules involved in MSC 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 targeted and untargeted migration of MSCs. The interaction of MSCs with activated ECs enhanced the paracrine activity of both cell types due to upregulated transcription and elevated levels of pleiotropic cytokines IL-6 and IL-8, and altered the protease–antiprotease balance. These data suggest that short-term interaction of MSCs with activated ECs may play an important role in tissue reparative and remodeling processes. Specifically, it may promote the migratory phenotype of MSCs. In contrast to physiological hypoxia (5% O₂), acute hypoxic stress (0.1% O₂, 24 h) attenuated the stimulatory effects of ECs on MSCs.