Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal Cells

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,...

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Main Authors: Katarzyna Zielniok, Anna Burdzinska, Beata Kaleta, Radoslaw Zagozdzon, Leszek Paczek
Format: Article
Language:English
Published: MDPI AG 2020-11-01
Series:Cells
Subjects:
Online Access:https://www.mdpi.com/2073-4409/9/11/2396
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spelling doaj-486a76c79ade46a28609557bac6274b32020-11-25T04:01:46ZengMDPI AGCells2073-44092020-11-0192396239610.3390/cells9112396Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal CellsKatarzyna Zielniok0Anna Burdzinska1Beata Kaleta2Radoslaw Zagozdzon3Leszek Paczek4Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, PolandDepartment of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, PolandDepartment of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, PolandDepartment of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, PolandDepartment of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, PolandThe 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: <i>IL24</i>, <i>IL1B</i>, <i>CXCL8</i>, <i>PDCD1LG1</i>, <i>PDCD1LG2</i>, <i>HIF1A</i>, <i>CCL2</i> and <i>IL6</i>, and upregulated <i>IL17RD</i>, <i>CCL28</i> and <i>LEP</i>. 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.https://www.mdpi.com/2073-4409/9/11/2396mesenchymal stem cellsVadadustatAKB-6548preconditioningprimingimmunomodulation
collection DOAJ
language English
format Article
sources DOAJ
author Katarzyna Zielniok
Anna Burdzinska
Beata Kaleta
Radoslaw Zagozdzon
Leszek Paczek
spellingShingle Katarzyna Zielniok
Anna Burdzinska
Beata Kaleta
Radoslaw Zagozdzon
Leszek Paczek
Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal Cells
Cells
mesenchymal stem cells
Vadadustat
AKB-6548
preconditioning
priming
immunomodulation
author_facet Katarzyna Zielniok
Anna Burdzinska
Beata Kaleta
Radoslaw Zagozdzon
Leszek Paczek
author_sort Katarzyna Zielniok
title Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal Cells
title_short Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal Cells
title_full Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal Cells
title_fullStr Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal Cells
title_full_unstemmed Vadadustat, a HIF Prolyl Hydroxylase Inhibitor, Improves Immunomodulatory Properties of Human Mesenchymal Stromal Cells
title_sort vadadustat, a hif prolyl hydroxylase inhibitor, improves immunomodulatory properties of human mesenchymal stromal cells
publisher MDPI AG
series Cells
issn 2073-4409
publishDate 2020-11-01
description 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: <i>IL24</i>, <i>IL1B</i>, <i>CXCL8</i>, <i>PDCD1LG1</i>, <i>PDCD1LG2</i>, <i>HIF1A</i>, <i>CCL2</i> and <i>IL6</i>, and upregulated <i>IL17RD</i>, <i>CCL28</i> and <i>LEP</i>. 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.
topic mesenchymal stem cells
Vadadustat
AKB-6548
preconditioning
priming
immunomodulation
url https://www.mdpi.com/2073-4409/9/11/2396
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