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

Alessandra Colombini; Francesca Libonati; Davide Cangelosi; Silvia Lopa; Paola De Luca; Domenico Antonio Coviello; Matteo Moretti; Laura de Girolamo

doi:10.3389/fbioe.2022.1000879

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

Front Bioeng Biotechnol. 2022 Oct 20:10:1000879. doi: 10.3389/fbioe.2022.1000879. eCollection 2022.

Authors

Alessandra Colombini¹, Francesca Libonati¹, Davide Cangelosi², Silvia Lopa³, Paola De Luca¹, Domenico Antonio Coviello⁴, Matteo Moretti^{3

5

6

7}, Laura de Girolamo¹

Affiliations

¹ Orthopaedic Biotechnology Lab, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
² Unità di Bioinformatica Clinica, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
³ Cell and Tissue Engineering Laboratory, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
⁴ Laboratorio di Genetica Umana, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
⁵ Regenerative Medicine Technologies Lab, Ente Ospedaliero Cantonale, Laboratories for Translational Research (LRT), Bellinzona, Switzerland.
⁶ Department of Surgery, Ente Ospedaliero Cantonale, Service of Orthopaedics and Traumatology, Lugano, Switzerland.
⁷ Faculty of Biomedical Sciences, Euler Institute, Lugano, Switzerland.

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.

Keywords: adipose derived stem cells; early osteoarthritis; immunomodulation; inflammatory priming; interleukin 1 beta.