Abstract
Emerging evidence suggests that myeloid-derived suppressor cells (MDSCs) have great potential as a novel immune intervention modality in the fields of transplantation and autoimmune diseases. Thus far, efforts to develop MDSC-based therapeutic strategies have been hampered by the lack of a reliable source of MDSCs. Here we show that functional MDSCs can be efficiently generated from mouse embryonic stem (ES) cells and bone marrow hematopoietic stem (HS) cells. In vitro-derived MDSCs encompass two homogenous subpopulations: CD1151Ly-6C1 and CD115+Ly-6C- cells. The CD115+Ly-6C + subset is equivalent to the monocytic Gr-1+CD115 +F4/80+ MDSCs found in tumor-bearing mice. In contrast, the CD115+Ly-6C- cells, a previously unreported population of MDSCs, resemble the granulocyte/macrophage progenitors developmentally. In vitro, ES- and HS-MDSCs exhibit robust suppression against T-cell proliferation induced by polyclonal stimuli or alloantigens via multiple mechanisms involving nitric oxide synthase-mediated NO production and interleukin (IL)-10. Impressively, they display even stronger suppressive activity and significantly enhance ability to induce CD4+CD25+Foxp3+ regulatory T-cell development compared with tumor-derived MDSCs. Furthermore, adoptive transfer of ES-MDSCs can effectively prevent alloreactive T-cell-mediated lethal graft-versus-host disease, leading to nearly 82% long-term survival among treated mice. The successful in vitro generation of MDSCs may represent a critical step toward potential clinical application of MDSCs.
Original language | English |
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Pages (from-to) | 620-632 |
Number of pages | 13 |
Journal | Stem Cells |
Volume | 28 |
Issue number | 3 |
DOIs | |
State | Published - 31 Mar 2010 |
Keywords
- Differentiation
- Graft-versus-host disease
- Mouse embryonic stem cells
- Mouse hematopoietic stem/progenitor cells
- Myeloid-derived suppressor cells