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

Abstract

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.

• Authors: Per Anderson, Luciana Souza-Moreira, Maria Morell, Marta Caro, Francisco O'Valle, Elena Gonzalez-Rey, Mario Delgado
• Journal: Gut (Gut) Vol. 62 Issue 8 Pg. 1131-41 (Aug 2013) ISSN: 1468-3288 [Electronic] England
• PMID: 22637701 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• Cytokines
• Inflammation Mediators

Topics

• Acute Disease
• Adipose Tissue (cytology)
• Animals
• Bone Marrow Cells (immunology)
• Cells, Cultured
• Coculture Techniques
• Colitis (chemically induced, immunology, pathology, prevention & control)
• Culture Media, Conditioned
• Cytokines (biosynthesis)
• Disease Models, Animal
• Humans
• Immunosuppression Therapy (methods)
• Inflammation Mediators (metabolism)
• Macrophage Activation (immunology)
• Macrophages (transplantation)
• Male
• Mesenchymal Stem Cells (immunology)
• Mice
• Mice, Inbred BALB C
• Sepsis (immunology, prevention & control)
• Systemic Inflammatory Response Syndrome (prevention & control)
• Treatment Outcome