Abstract
The therapeutic potential of mesenchymal stromal cells (MSCs) is largely attributed to their immunomodulatory properties, which can be further improved by hypoxia priming. In this study, we investigated the immunomodulatory properties of MSCs preconditioned with hypoxia-mimetic Vadadustat (AKB-6548, Akebia). Gene expression analysis of immunomodulatory factors was performed by real-time polymerase chain reaction (real-time PCR) on RNA isolated from six human bone-marrow derived MSCs populations preconditioned for 6 h with 40 μM Vadadustat compared to control MSCs. The effect of Vadadustat preconditioning on MSCs secretome was determined using Proteome Profiler and Luminex, while their immunomodulatory activity was assessed by mixed lymphocyte reaction (MLR) and Culturex transwell migration assays. Real-time PCR revealed that Vadadustat downregulated genes related to immune system: IL24, IL1B, CXCL8, PDCD1LG1, PDCD1LG2, HIF1A, CCL2 and IL6, and upregulated IL17RD, CCL28 and LEP. Vadadustat caused a marked decrease in the secretion of IL6 (by 51%), HGF (by 47%), CCL7 (MCP3) (by 42%) and CXCL8 (by 40%). Vadadustat potentiated the inhibitory effect of MSCs on the proliferation of alloactivated human peripheral blood mononuclear cells (PBMCs), and reduced monocytes-enriched PBMCs chemotaxis towards the MSCs secretome. Preconditioning with Vadadustat may constitute a valuable approach to improve the therapeutic properties of MSCs.
Highlights
Human mesenchymal stromal cells (MSCs) therapy has shown a promising potential in the treatment of diseases associated with immune-mediated disorders
The plasticity of MSCs immunomodulation is associated with the ability to elicit markedly different modulatory responses, which results from the current state of inflammatory mediators in their microenvironment
The effect of HIF-1α stabilization by hypoxia mimetic agents on MSCs properties has already been studied (cobalt chloride, deferoxamine, ciclopirox olamine, N-acetylcysteine, FG-4497, AKB-4924 [29,30,31,32,33], we used for the first time Vadadustat (AKB-6548)—a novel oral PHD2 inhibitor tested in phase III clinical trials that works through the mechanism of active site iron chelation in the submicromolar range [15]
Summary
Human mesenchymal stromal cells (MSCs) therapy has shown a promising potential in the treatment of diseases associated with immune-mediated disorders (reviewed in [1]). Despite the lack of sufficient data explaining the native, physiological function of MSCs in the human body, existing experimental results demonstrate their multipotency [2] and considerable paracrine-mediated immunosuppressive and inflammation resolving activity (reviewed in [3]). A fundamental shift was made from the initially proposed paradigm of reparative function of MSCs, to the paradigm of MSCs modulating activity, manifested by secretion of numerous bioactive compounds regulating immune response and contributing to tissue regeneration. The outstanding potential of MSCs lies in their ability to home to the site of damage and crosstalk with other types of cell in order to limit cell death, diminish an excessive inflammatory response and facilitate the intrinsic tissue regeneration capacity
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