Magnetic Stimulation Drives Macrophage Polarization in Cell to-Cell Communication with IL-1β Primed Tendon Cells.

Ana I. Gonçalves,Adriana Vinhas,Manuela E. Gomes,Ana F. Almeida,Márcia T. Rodrigues

doi:10.3390/ijms21155441

Ana I. Gonçalves, Adriana Vinhas + Show 3 more

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https://doi.org/10.3390/ijms21155441

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Abstract

Inflammation is part of the natural healing response, but it has been simultaneously associated with tendon disorders, as persistent inflammatory events contribute to physiological changes that compromise tendon functions. The cellular interactions within a niche are extremely important for healing. While human tendon cells (hTDCs) are responsible for the maintenance of tendon matrix and turnover, macrophages regulate healing switching their functional phenotype to environmental stimuli. Thus, insights on the hTDCs and macrophages interactions can provide fundamental contributions on tendon repair mechanisms and on the inflammatory inputs in tendon disorders. We explored the crosstalk between macrophages and hTDCs using co-culture approaches in which hTDCs were previously stimulated with IL-1β. The potential modulatory effect of the pulsed electromagnetic field (PEMF) in macrophage-hTDCs communication was also investigated using the magnetic parameters identified in a previous work. The PEMF influences a macrophage pro-regenerative phenotype and favors the synthesis of anti-inflammatory mediators. These outcomes observed in cell contact co-cultures may be mediated by FAK signaling. The impact of the PEMF overcomes the effect of IL-1β-treated-hTDCs, supporting PEMF immunomodulatory actions on macrophages. This work highlights the relevance of intercellular communication in tendon healing and the beneficial role of the PEMF in guiding inflammatory responses toward regenerative strategies.

Highlights

Tendon pathologies are among the most debilitating orthopedic problems due to poor tissue response to currently available treatments, affecting both elderly and active populations
Since we were exploring the effect of magnetic stimuli and IL-1β conditioned cells in the modulation of the heterotopic cell crosstalk, we investigated indirect co-cultures to confirm if cell metabolic activity and the gene transcripts of tendon and immune-associated markers were not more affected by paracrine effects rather than cellular interactions
The co-culture models were subjected to either the control basal medium (Ctrl) or medium supplemented with IL-1β cytokine (IL-1β)

Summary

Introduction

Tendon pathologies are among the most debilitating orthopedic problems due to poor tissue response to currently available treatments, affecting both elderly and active populations. Persistent inflammatory events may lead to chronic/degenerative changes in tendon structure, impairing tissue functionality and increasing the risk of re-injury [1,2]. In an initial response, activated macrophages (M1 subtype) are responsible for the release of pro-inflammatory cytokines (e.g., TNFα, IL-1β, IL-6, IL-12, IL-23), trophic factors as chemokines and signaling molecules into the repair site in order to promote inflammation, extracellular matrix (ECM) degradation, and debris clearance. Pro-regenerative macrophages (M2 subtype) coordinate ECM deposition, secreting anti-inflammatory mediators (e.g., IL-4, IL-10, IL-13, TGFβ) and cell-attracting chemokines (e.g., CCL17, CCL22, and CCL24) to attenuate and assist the resolution of inflammatory events and promote tendon repair [5,6,7]

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