Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis

Stem Cells. 2011 Oct;29(10):1549-58. doi: 10.1002/stem.698.

Abstract

Mesenchymal stromal cells (MSCs) are currently under investigation for the treatment of inflammatory disorders, including Crohn's disease. MSCs are pluripotent cells with immunosuppressive properties. Recent data suggest that resting MSCs do not have significant immunomodulatory activity, but that the immunosuppressive function of MSCs has to be elicited by interferon-γ (IFN-γ). In this article, we assessed the effects of IFN-γ prestimulation of MSCs (IMSCs) on their immunosuppressive properties in vitro and in vivo. To this end, we pretreated MSCs with IFN-γ and assessed their therapeutic effects in dextran sodium sulfate (DSS)- and trinitrobenzene sulfonate (TNBS)-induced colitis in mice. We found that mice treated with IMSCs (but not MSCs) showed a significantly attenuated development of DSS-induced colitis. Furthermore, IMSCs alleviated symptoms of TNBS-induced colitis. IMSC-treated mice displayed an increase in body weight, lower colitis scores, and better survival rates compared with untreated mice. In addition, serum amyloid A protein levels and local proinflammatory cytokine levels in colonic tissues were significantly suppressed after administration of IMSC. We also observed that IMSCs showed greater migration potential than unstimulated MSCs to sites within the inflamed intestine. In conclusion, we show that prestimulation of MSCs with IFN-γ enhances their capacity to inhibit Th1 inflammatory responses, resulting in diminished mucosal damage in experimental colitis. These data demonstrate that IFN-γ activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Cell Differentiation
  • Cell Movement
  • Colitis / chemically induced
  • Colitis / pathology
  • Colitis / therapy*
  • Colon / immunology
  • Colon / pathology
  • Cytokines / analysis
  • Dextran Sulfate / adverse effects
  • Disease Models, Animal
  • Female
  • Humans
  • Immunity, Cellular
  • Immunosuppression
  • Injections, Intraperitoneal
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Serum Amyloid A Protein / analysis
  • Trinitrobenzenesulfonic Acid / adverse effects

Substances

  • Cytokines
  • Serum Amyloid A Protein
  • Interferon-gamma
  • Trinitrobenzenesulfonic Acid
  • Dextran Sulfate