Toll-like receptor 3 pre-conditioning increases the therapeutic efficacy of umbilical cord mesenchymal stromal cells in a dextran sulfate sodium-induced colitis model

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• 作者：Patricia Fuenzalida¹ ; Mó ; nica Kurte¹ ; Catalina Ferná ; ndez-O'ryan¹ ; Cristina Ibañ ; ez¹ ; Melanie Gauthier-Abeliuk¹ ; Ana Marí ; a Vega-Letter¹ ; Paz Gonzalez² ; ³ ; Carlos Irarrá ; zabal⁴ ; Nataly Quezada¹ ; Fernando Figueroa¹ ; Flavio Carrió ; n¹ ; ^{fcarrion@uandes.cl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：cell therapy ; dextran sulfate sodium&ndash ; induced colitis ; immunosuppression ; inflammatory bowel disease ; toll-like receptors ; umbilical cord&ndash ; derived mesenchymal stromal cells
• 刊名：Cytotherapy
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：18
• 期：5
• 页码：630-641
• 全文大小：1729 K

文摘

Immunomodulatory properties of human umbilical cord–derived mesenchymal stromal cells (UCMSCs) can be differentially modulated by toll-like receptors (TLR) agonists. Here, the therapeutic efficacy of short TLR3 and TLR4 pre-conditioning of UCMSCs was evaluated in a dextran sulfate sodium (DSS)-induced colitis in mice. The novelty of this study is that although modulation of human MSCs activity by TLRs is not a new concept, this is the first time that short TLR pre-conditioning has been carried out in a murine inflammatory model of acute colitis.

Methods

C57BL/6 mice were exposed to 2.5% dextran sulfate sodium (DSS) in drinking water ad libitum for 7 days. At days 1 and 3, mice were injected intraperitoneally with 1 × 10⁶ UCMSCs untreated or TLR3 and TLR4 pre-conditioned UCMSCs. UCMSCs were pre-conditioned with poly(I:C) for TLR3 and LPS for TLR4 for 1 h at 37°C and 5% CO₂. We evaluated clinical signs of disease and body weights daily. At the end of the experiment, colon length and histological changes were assessed.

Results

poly(I:C) pre-conditioned UCMSCs significantly ameliorated the clinical and histopathological severity of DSS-induced colitis compared with UCMSCs or LPS pre-conditioned UCMSCs. In contrast, infusion of LPS pre-conditioned UCMSCs significantly increased clinical signs of disease, colon shortening and histological disease index in DSS-induced colitis.

Conclusions

These results show that short in vitro TLR3 pre-conditioning with poly(I:C) enhances the therapeutic efficacy of UCMSCs, which is a major breakthrough for developing improved treatments to patients with inflammatory bowel disease.