IntroductionMesenchymal stem cells (MSCs) are important tools in treating immune disorders and in tissue repair by their multipotency, immunosuppressive properties, and production of cytokines or growth factors, Many sources of MSCs have been described and the main candidates for clinical application are bone marrow and adipocyte tissues widely available and easy to collect by standardized procedures. However, as they have in vitro and in vivo time-limited functions, 1,2 several research groups are searching for MSCs with prolonged lifetime and immunoregulatory properties. In the last decade, MSCs have been isolated from fetal or neonatal tissues [3][4][5][6][7] and embryonic tissues (ES-MSCs). [8][9][10] At present, no specific markers for the origin of the MSCs have been identified and all types of MSCs are defined by their CD105, CD90, CD73, CD44, CD29, CD146, and CD166 expression. Adult BM-MSCs exhibit immunomodulatory functions on immune cells by both cell-cell contact and soluble factors. 2,[11][12][13] Recently, human somatic cells have been successfully reprogrammed into induced pluripotent cells (iPSC) [14][15][16][17][18][19] that exhibit characteristics similar to human ES. 20 IPSC hold enormous promise for personalized cellreplacement therapy 21 and for research into various human diseases. 22,23 Therefore, MSCs derived from iPSC may be a novel source of tolerance induction, though their immunosuppressive activity remains to be explored.We report that MSCs isolated from diverse human iPS Cell lines (iPS-MSCs) can strongly inhibit the cytotoxic functions of natural killer (NK) cells. Most of these MSC-mediated inhibitory effects are because of a general impairment of NK activation and disruption of the secretory machinery on NK cells. Interestingly, iPS-MSCs and ES-MSCs are more resistant than BM-MSCs to preactivated NK cells. Our current data indicate that iPS-MSCs could represent a promising alternative strategy for the treatment of various immune-mediated diseases.
Methods
ReagentsThe antibodies used to assess NK and MSC phenotypes are described in supplemental Table 1 (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Recombinant human IL-2 was purchased from Immunotools, whereas Mitomycin, Monensin, and Brefaldin were purchased from Sigma-Aldrich. 1-Methyl-tryptophan (1-MT) and NS-398, specific inhibitors for Indoleamine 2,3-dioxygenase (IDO) and Prostaglandin (PGE)-2, respectively, were also purchased from Sigma-Aldrich. 87G antagonist antibody anti-HLA-G was purchased from Exbio.
Pluripotent stem-cell linesWe used 3 human iPS cell lines PB3, PB10, and PB11 provided from the Stem cell Core-Facility (ES Team Paris Sud, University Paris 11, Villejuif, France) that were derived from amniotic fluid cells (AFC-iPS) after amniocentesis (Antoine Béclère Hospital, Clamart France). Their pluripotency was validated by teratoma assay, flow cytometry and RT-PCR and registered into the European Registry Web site (http://www.hescreg.eu). In addition, we de...
