Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis

Abstract

Background and Aims: Inflammatory bowel diseases (IBD) are associated with uncontrolled innate and adaptive immunity against normal constituents, including commensal bacteria and microbial products. Mesenchymal stem cells (MSCs) suppress effector T-cell responses and have beneficial effects in various immune disorders. This work investigates the therapeutic effects of human adipose-derived MSCs (hASCs) in various models of IBD and sepsis.

Methods: Acute and chronic colitis was induced in mice with dextran sulphate sodium. Sepsis was induced by cecal ligation and puncture or by endotoxin injection. Colitic and septic mice were treated i.p. with hASCs or murine ASCs, and determined diverse disease clinical signs and mortality. The levels of various inflammatory cytokines and chemokines, Th1-type response, and generation of regulatory T (Treg) were determined in affected organs.

Results: Systemic infusion of ASCs significantly ameliorated the clinical and histopathologic severity of colitis, abrogating weight loss, diarrhoea, and inflammation, and increasing survival. The therapeutic effect was associated with down-regulation of the Th1-driven inflammatory responses. ASCs decreased a wide panel of inflammatory cytokines and chemokines and increased IL-10, acting on macrophages. hASCs also impaired Th1-cell activation in both colonic mucosa and draining lymph nodes. The induction of IL-10-secreting Treg was partially involved in the therapeutic effect of hASCs. Moreover, ASCs protected from severe sepsis by reducing the infiltration of inflammatory cells in various target organs and by down-regulating the production of various inflammatory mediators.

Conclusions: hASCs emerge as key regulators of immune/inflammatory responses in vivo and as attractive candidates for cell-based therapies to treat IBD and sepsis.