MESENCHYMAL-STEM-CELL-INDUCED IMMUNOREGULATION INVOLVES FAS-LIGAND-/FAS-MEDIATED T CELL APOPTOSIS.
|Journal:||Cell Stem Cell|
|Year of Publication:||2012|
|Authors:||Yasufumi Umena, Keisuke Kawakami, Jian-Ren She, and Nobuo Kamiya|
Systemic infusion of bone marrow mesenchymal stem cells (BMMSCs) yields therapeutic benefit for a variety of autoimmune diseases, but the underlying mechanisms are poorly understood. Here we show that in mice systemic infusion of BMMSCs induced transient T cell apoptosis via the FAS ligand (FASL)-dependent FAS pathway and could ameliorate disease phenotypes in fibrillin-1 mutated systemic sclerosis (SS) and dextran-sulfate-sodium-induced experimental colitis. FASL -/- BMMSCs did not induce T cell apoptosis in recipients, and could not ameliorate SS and colitis. Mechanistic analysis revealed that FAS-regulated monocyte chemotactic protein 1 (MCP-1) secretion by BMMSCs recruited T cells for FASL-mediated apoptosis. The apoptotic T cells subsequently triggered macrophages to produce high levels of TGFβ, which in turn led to the upregulation of CD4 +CD25 +Foxp3 + regulatory T cells and, ultimately, immune tolerance. These data therefore demonstrate a previously unrecognized mechanism underlying BMMSC-based immunotherapy involving coupling via FAS/FASL to induce T cell apoptosis.
- Mesenchymal Stromal Cells, Bone Marrow, Apoptosis, Immunotherapy