Immunomodulatory\nBehavior of Tendon Magnetic Cell\nSheets can be Modulated in Hypoxic Environments under Magnetic Stimulus

Tissue\nenvironments play a crucial role in orchestrating\ncell behavior,\nguided by a complex interplay of various factors. Long lasting inflammatory\nsignals compromise tendon homeostasis and promote tissue degeneration,\nwhile tissue oxygen levels affect local cells’ responses with\nhypoxic environments influencing apoptosis, inflammatory mediators,\nand matrix production. Recent works have unveiled the therapeutic\npotential of pulsed electromagnetic field (PEMF) in modulating inflammatory\nsignals expressed by human tendon cells (hTDCs), and in mitigating\nthe hypoxia-induced effects on the regulation of inflammatory cytokines.\nThus, we sought to investigate the role of hypoxic environments, namely,\n1 and 2% oxygen tension, in the inflammatory profiles of magnetic\ncell sheets (magCSs) formed by magnetic nanoparticles internalized\nin contiguous hTDCs with intact cell–cell junctions and deposited\nmatrix. We also aimed to explore the impact of PEMF over hypoxia-treated\nmagCSs, including IL-1β-primed-magCSs, with the objective of\nharnessing magnetic stimulation to guide abnormal inflammatory cell\nresponses toward efficient treatments supporting tendon regenerative\npotential. Our findings revealed that low oxygen tensions amplified\nthe expression of hypoxia-associated genes and of inflammatory markers\nin IL-1β-primed-magCSs with an involvement of the NF-κB\nsignaling pathway. Encouragingly, when PEMF was applied to IL-1β-primed-magCSs\nunder hypoxic conditions, it successfully modulated inflammatory cues\nby favoring IL-10 and IL-4, via the NF-κB pathway. These results\nsignify the remarkable potential of PEMF in driving proregenerative\nstrategies and opens up new approaches in tendon therapies, highlighting\nthe transformative impact of immunomodulatory magnetic cell sheets.