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Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis

结肠炎 间充质干细胞 败血症 炎症 免疫学 医学 骨髓 癌症研究 脂肪组织 间质细胞 体外 巨噬细胞 化学 病理 内科学 生物化学
作者
Per Anderson,Luciana Souza‐Moreira,María Morell,Marta Caro,Francisco O’Valle,Elena González‐Rey,Mario Delgado
出处
期刊:Gut [BMJ]
卷期号:62 (8): 1131-1141 被引量:191
标识
DOI:10.1136/gutjnl-2012-302152
摘要

Objective

To investigate the effect of adipose-derived mesenchymal stromal cells (ASCs) on the activation state of macrophages (MΦ) in vitro, and the potential therapeutic effect of these cells in experimental colitis and sepsis.

Design

Murine bone marrow-derived macrophages were cultured with ASCs or with ASC conditioned media (ASC-MΦ) and characterised for the expression of several regulatory macrophage markers, including enzymes and cytokines, and for their immunomodulatory capacity in vitro. The therapeutic effect was investigated of ASC-MΦ in two models of experimental inflammatory colitis induced by trinitrobenzene sulphonic acid and dextran sodium sulphate, and in polymicrobial sepsis induced by caecal ligation and puncture.

Results

ASC-MΦ showed a phenotype that clearly differed from the classically activated macrophages or the alternatively activated macrophages induced by interleukin (IL)-4, characterised by high arginase activity, increased production of IL-10 upon restimulation and potent immunosuppressive activity on T cells and macrophages. Activation of cyclo-oxygenase-2 on ASCs seems to be critically involved in inducing this phenotype. Systemic infusion of ASC-MΦ inhibited colitis in mice, reducing mortality and weight loss while lowering the colonic and systemic levels of inflammatory cytokines. Importantly, therapeutic injection of ASC-MΦ in established chronic colitis alleviated its progression and avoided disease recurrence. Moreover, ASC-MΦ protected from severe sepsis by reducing the infiltration of inflammatory cells into various organs and by downregulating the production of several inflammatory mediators, where ASC-MΦ-derived IL-10 played a critical role.

Conclusion

ASCs induce a distinct regulatory activation state of macrophages which possess potent immunomodulatory ability and therapeutic potential in inflammatory bowel diseases and sepsis.
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