Background/Purpose: Immunomodulatory properties enable mesenchymal stem cells (MSCs) to be a promising alternative for the treatment of a wide range of immune-related diseases including rheumatoid arthritis (RA). However, underlying mechanisms with the perspective of systemic immune regulation are less verified. We sought to explore the therapeutic efficacy of human umbilical cord blood-derived MSCs (hUCB-MSCs) against murine collagen-induced arthritis (CIA) and to investigate distinct mechanisms mainly focused on macrophages.

Methods: CIA was induced in DBA1/J mice by the repeated immunization of bovine type II collagen with complete Freund’s adjuvant. hUCB-MSCs were administered to CIA mice intraperitoneally each day for 5 days after the onset of disease, and clinical severity was assessed. Alternatively, CIA mice were given with a single intravenous injection of hUCB-MSCs at the same phase of disease progression. To verify the regulatory effects of hUCB-MSCs on macrophages, human and murine macrophages were co-cultured with hUCB-MSCs and the alteration of cytokine profile and marker expression was determined. These regulatory functions were confirmed using peripheral blood mononuclear cells (PBMCs) from patients with RA.

Results: The multiple intraperitoneal administration of hUCB-MSCs exerted significant therapeutic efficacy against CIA to a similar extent of etanercept, anti-TNF-α biologic agent. A single intravenous injection of hUCB-MSCs exerted sufficient therapeutic effect on CIA, and down-regulated the production of various pro-inflammatory cytokines concomitantly. hUCB-MSCs suppressed the classical M1 activation of macrophages, and simultaneously increased the anti-inflammatory M2 polarization. Concerted action of strengthened cyclooxygenase (COX-2) and tumor necrosis factor alpha stimulate gene 6 (TSG-6) signaling in response to TNF-α, a prominent inflammatory cytokine in RA, contributed to the regulation of macrophage plasticity by inducing M2 polarization. In addition, these immune-balancing effects of hUCB-MSCs were reproducible in PBMCs from patients with active RA.

Conclusion: The systemic application of hUCB-MSCs can effectively attenuate murine inflammatory arthritis through the regulation of macrophage plasticity. Upon TNF-α stimuli, COX-2 and TSG-6 signaling is enhanced, consequentially results in both inhibition of M1 activation and induction of M2 polarization. Therefore, our findings provide the clue that stem cell therapy using hUCB-MSCs can be an attractive candidate for the treatment of RA, especially who do not respond to current single-target biologic medications.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/human-umbilical-cord-blood-derived-mesenchymal-stem-cells-ameliorate-rheumatoid-arthritis-via-regulation-of-macrophage-activation-and-polarization/