Inflammatory priming with IL-1β promotes the immunomodulatory behavior of adipose derived stem cells

Abstract

Inflammatory processes contribute to osteoarthritis (OA) severity and progression. Mesenchymal stem cells, particularly those derived from adipose tissue (ASCs), are able to sense and control the inflammatory environment. This immunomodulatory potential can be boosted by different priming strategies based on inflammatory stimulation. The aim of the present study is to investigate the transcriptional modulation of a huge panel of genes and functionally verify the predicted immunomodulatory ability of ASCs after interleukin one beta (IL-1β) priming. ASCs were isolated from adipose tissue obtained from three donors and expanded. After stimulation with 1 ng/ml of IL-1β for 48 h, cells were collected for gene array and functional tests. Pooled cells from three donors were used for RNA extraction and gene array analysis. Gene Ontology (GO) enrichment analysis and Gene Set Enrichment Analysis (GSEA) were performed to assess the involvement of the modulated genes after priming in specific biological processes and pathways. Functional co-culture tests of ASCs with T cells and macrophages were performed to assess the ability of primed ASCs to modulate immune cell phenotype. Among the overall genes analyzed in the gene array, about the 18% were up- or down-regulated in ASCs after IL-1β priming. GO enrichment analysis of up- or down-regulated genes in ASCs after IL-1β priming allowed identifying specific pathways involved in the modulation of inflammation and extracellular matrix remodeling. The main processes enriched according to the GSEA are related to the inflammatory response and cell proliferative processes. Functional tests on immune cells showed that primed and non-primed ASCs induced a decrease in the CD3+ T lymphocytes survival rate and an anti-inflammatory macrophage polarization. In conclusion, IL-1β priming represents a tailored strategy to enhance the ability of ASCs to direct macrophages towards an anti-inflammatory phenotype and, consequently, improve the efficacy of ASCs in counteracting the OA inflammatory component.

Women’s contribution to stem cell research for osteoarthritis: an opinion paper

“…The immunomodulatory capacity of MSCs and ASCs can be influenced by disease status of the joint as noted by the groups of G. J. V. M. van Osch* and of G. Lisignoli* (Leijs et al, 2012;Manferdini et al, 2020). The immunomodulatory ability of ASCs was not affected by hypoxia as reported by the group of G. J. V. M. van Osch* (Roemeling-van Rhijn et al, 2013), whereas it was positively affected by an inflammatory stimulus such as interleukin 1 beta (IL-1β) as observed by the groups of L. de Girolamo* and of D. Noël* (Colombini et al, 2022b;Maumus et al, 2016). Similarly, the protein cargo of umbilical cord EVs was affected by their pro-inflammatory priming, but not in hypoxic conditions (Hyland et al, 2020).…”

Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells

“…Most HUC-MSCs were dead and then quickly phagocytosed by monocytes after 24 h. Cocultured studies of MSCs either using a transwell or directly with two kinds of NK cell lines demonstrated that granule polarization is either induced or restrained through the special crosstalk of MSCs on the two NK cell lines [ 97 ]. Moreover, some studies found that AMSCs can switch an activated-M1 pro-inflammatory phenotype of macrophages to its anti-inflammatory M2 phenotype associated with the specific function of prostaglandin E2 (PGE2) [ 98 , 99 ]. Furthermore, MSCs hold substantial therapeutic promise to prevent unrestrained neutrophil activation-induced tissue damage depending on the neutrophils’ engulfment of intercellular adhesion molecule-1 (IAM-1) derived from MSCs [ 100 , 101 ].…”

Factors Defining Human Adipose Stem/Stromal Cell Immunomodulation in Vitro

“…Regarding treatment with IL-1β, priming of hASCs from patients with osteoarthritis (OA) with this cytokine (1 ng/ml for 24 h) induced the differential expression of genes enriched in inflammation modulation and extracellular matrix (ECM) remodeling. Moreover, compared to non-primed cells, IL-1β primed hASCs superiorly modulated the CD80 + /CD206 + cell ratio in co-culture with polarized M1 macrophages, promoting an increase of the anti-inflammatory CD206 + M2a macrophages [ 112 ].…”

“…The impact of inflammatory diseases on the immunosuppressive properties of hASCs has been extensively investigated to include RD [ 46 , 47 , 96 , 112 , 231 , 247 – 257 ], T2D [ 67 , 109 , 156 , 258 ], sepsis [ 259 ], Crohn’s disease [ 260 – 263 ], ulcerative colitis [ 264 ], breast cancer [ 265 – 269 ], osteoporosis [ 270 ], psoriasis vulgaris [ 140 ], Parkinson's disease [ 271 ], and atherosclerosis [ 272 ]. The results are contradictory from diseased ASCs having intact immunomodulatory functions to impaired immunosuppressive effects.…”

“…Regarding the immunosuppressive potential of ASCs isolated from patients with RD, controversial data have been reported from mostly intact [ 47 , 112 , 254 , 273 ], to affected [ 250 ], ASC immunosuppressive functions. RD/ASCs (from patients with SLE, SSc, or AS) were characterized by low basal levels of CD90 and ICAM-1 expression, upregulated secretion of IL-1Ra, TSG-6 and sHLA-G, but impaired release of kynurenines and galectin-3 [ 252 ].…”