Original Article

Citation: Cell Death and Disease (2016) 7, e2524; doi:10.1038/cddis.2016.442
Published online 22 December 2016

Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis
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Tae-Hoon Shin1,2,5, Hyung-Sik Kim1,5,6,7, Tae-Wook Kang3, Byung-Chul Lee1,2, Hwa-Yong Lee3,8, Yoon-Jin Kim3, Ji-Hee Shin1,2, Yoojin Seo1,6,7, Soon Won Choi1,2, Seunghee Lee3, Kichul Shin4, Kwang-Won Seo3 and Kyung-Sun Kang1,2

  1. 1Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
  2. 2Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
  3. 3Institute for Stem Cell and Regenerative Medicine in Kangstem Biotech, Biomedical Science Building, Seoul National University, Seoul, Republic of Korea
  4. 4Division of Rheumatology, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea

Correspondence: K-S Kang, Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea. Tel: +82 2 880 1246; Fax: +82 2 876 7610; E-mail: kangpub@snu.ac.kr

5These authors contributed equally to this work.

6Current address: Biomedical Research Institute, Pusan National University Hospital, Pusan, Republic of Korea.

7Current address: Pusan National University School of Medicine, Pusan, Republic of Korea.

8Current address: The Faculty of Liberal Arts, Jungwon University, Chungcheongbuk-do, Republic of Korea.

Received 13 September 2016; Accepted 4 November 2016

Edited by H-U Simon

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Abstract

Rheumatoid arthritis (RA) is a long-lasting intractable autoimmune disorder, which has become a substantial public health problem. Despite widespread use of biologic drugs, there have been uncertainties in efficacy and long-term safety. Mesenchymal stem cells (MSCs) have been suggested as a promising alternative for the treatment of RA because of their immunomodulatory properties. However, the precise mechanisms of MSCs on RA-related immune cells are not fully elucidated. The aim of this study was to investigate the therapeutic potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) as a new therapeutic strategy for patients with RA and to explore the mechanisms underlying hUCB-MSC-mediated immunomodulation. Mice with collagen-induced arthritis (CIA) were administered with hUCB-MSCs after the onset of disease, and therapeutic efficacy was assessed. Systemic delivery of hUCB-MSCs significantly ameliorated the severity of CIA to a similar extent observed in the etanercept-treated group. hUCB-MSCs exerted this therapeutic effect by regulating macrophage function. To verify the regulatory effects of hUCB-MSCs on macrophages, macrophages were co-cultured with hUCB-MSCs. The tumor necrosis factor (TNF)-α-mediated activation of cyclooxygenase-2 and TNF-stimulated gene/protein 6 in hUCB-MSCs polarized naive macrophages toward an M2 phenotype. In addition, hUCB-MSCs down-regulated the activation of nucleotide-binding domain and leucine-rich repeat pyrin 3 inflammasome via a paracrine loop of interleukin-1β signaling. These immune-balancing effects of hUCB-MSCs were reproducible in co-culture experiments using peripheral blood mononuclear cells from patients with active RA. hUCB-MSCs can simultaneously regulate multiple cytokine pathways in response to pro-inflammatory cytokines elevated in RA microenvironment, suggesting that treatment with hUCB-MSCs could be an attractive candidate for patients with treatment-refractory RA.