Immunomodulatory effects of bone marrow mesenchymal stem cells overexpressing heme oxygenase-1: Protective effects on acute rejection following reduced-size liver transplantation in a rat model

• Published in: Cellular immunology 2017-03, Vol.313, p.10-24
• Main Authors: Shen, Zhong-Yang, Wu, Bin, Liu, Tao, Yang, Yang, Yin, Ming-Li, Zheng, Wei-Ping, Zhang, Bo-Ya, Song, Hong-Li
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; BM MSCS; Cells, Cultured; Graft Rejection - immunology; Graft Rejection - prevention & control; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; HO-1; Immunomodulation; Liver Transplantation; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - physiology; Rats; Rats, Inbred Lew; Rejection; T-Lymphocytes, Regulatory - immunology; Th1-Th2 Balance; Th17 Cells - immunology; Transgenes - genetics; Transplantation Tolerance; Transplantation, Homologous
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2016.12.006

•Overexpression of HO-1 in BMMSCs increased their immunomodulatory effects.•BMMSCs overexpressing HO-1 regulated immune cells.•This involved Th1/Th2 balance, Th17 to Treg induction, and killer cell inhibition.•Adv-HO-1/BMMSCs were tested in a reduced-size liver transplantation rejection model.•The Adv-HO-1/BMMSCs had immunosuppressive effects and protected liver allografts. Here we explore the T-lymphocyte suppressive and immunomodulatory effects of bone marrow mesenchymal stem cells (BMMSCs) overexpressing heme oxygenase-1 (HO-1) on acute rejection following reduced-size liver transplantation (RLT) in a rat model. The proliferation activity, cell cycle progression, secretion of proinflammatory cytokines, expression of CD25 and CD71 in lymphocytes, and activity of NK cells were found to be significantly lowered, and the proportion of regulatory T cells (Tregs) was found to be increased relative to BMMSCs when Adv-HO-1/BMMSCs were co-cultured with Con A ex vivo; secretion of anti-inflammatory cytokines was significantly higher. When treated with saline, BMMSCs or Adv-HO-1/BMMSCs, post-transplantation rats receiving Adv-HO-1/BMMSCs showed better median survival time, lower rejection activity index, higher anti-inflammatory cytokine levels, lower proinflammatory cytokine levels, more peripheral Tregs, and lower natural killer cell viability. These results suggest that HO-1 enhanced and prolonged the effects of BMMSCs on acute rejection following RLT, with immunomodulatory effects in which adaptive and innate immunity, as well as paracrine signaling, may play important roles.