Mesenchymal stromal cells derived from CD271(+) bone marrow mononuclear cells exert potent allosuppressive properties.

BACKGROUND AIMS. Because data on the immunosuppressive effect of different subsets of mesenchymal stromal cells (MSC) are sparse, we investigated the molecular and cellular mechanisms underlying the allosuppressive effect of MSC generated from bone marrow CD271(+) cells (CD271-MSC) and asked whether this potential is comparable with that of MSC generated through plastic adherence (PA-MSC). METHODS. The immunosuppressive effect of CD271-MSC on the allogeneic reaction was investigated by mixed lymphocyte reaction (MLR). RESULTS. CD271-MSC significantly suppressed the alloantigen-induced proliferation of mononuclear cells (MNC) of two HLA-disparate donors at all MSC:MNC ratios, 1:1, 1:2 and 1:10. They also demonstrated a significantly higher allosuppression than PA-MSC at an MSC:MNC ratio of 1:1. This inhibitory effect was associated with significantly elevated levels of prostaglandin E2 (PGE2) at ratios of 1:1 and 1:2 (about 4-fold), but not at a ratio of 1:10. Indomethacin, and inhibitor of cyclooxygenase-1 and 2 necessary for the biosynthesis of PGE2, mitigated suppressive effects of CD271-MSC only at a ratio of 1:1, indicating that PGE2 is not involved in MSC-mediated inhibition when allogeneic MNC are in excess. The increase of PGE2 was associated with a significant decrease of pro-inflammatory cytokine levels (interferon-gamma and tumor necrosis-alpha), while no changes in levels of interleukin-10, soluble HLA-G and nitric oxide were observed. In addition, CD271-MSC induced an expansion of highly suppressive naive CD4(+)CD25(high)CD45RA(+)CD62L(+) T-regulatory cells, which may extend their allosuppressive effect. CONCLUSIONS. Our data suggest that CD271-MSC exert potent allosuppressive properties and therefore can be used as a reasonable alternative to PA-MSC for the treatment of patients with graft-versus-host disease.

CD271 antigen defines a subset of multipotent stromal cells with immunosuppressive and lymphohematopoietic engraftment-promoting properties.

UNLABELLED: Background In vitro proliferative and differentiation potential of mesenchymal stromal cells generated from CD271(+) bone marrow mononuclear cells (CD271-mesenchymal stromal cells) has been demonstrated in several earlier and recent reports. In the present study we focused, in addition to proliferative and differentiation potential, on in vitro and in vivo immunosuppressive and lymphohematopoietic engraftment-promoting potential of these mesenchymal stromal cells compared to bone marrow-derived mesenchymal stromal cells generated by plastic adherence (plastic adherence-mesenchymal stromal cells). DESIGN AND METHODS: We set up a series of experimental protocols in order to determine the phenotype of CD271-mesenchymal stromal cells, and their clonogenic, proliferative, differentiation and immunosuppressive potential. The potential of CD271-mesenchymal stromal cells to improve the engraftment of CD133(+) hematopoietic stem cells at co-transplantation was evaluated in immunodeficient NOD/SCID-IL2Rgamma(null) mice. RESULTS: In vitro studies demonstrated that CD271-mesenchymal stromal cells differentiate along adipogenic, osteogenic and chondrogenic lineages (trilineage potential), produce significantly higher levels of cytokines than plastic adherence-mesenchymal stromal cells, and significantly inhibit the proliferation of allogeneic T-lymphocytes in mixed lymphocyte reaction assays. Elevated levels of prostaglandin E(2), but not nitric monoxide, mediated the majority of this immunosuppressive effect. In vivo studies showed that CD271-mesenchymal stromal cells promoted significantly greater lymphoid engraftment than did plastic adherence-mesenchymal stromal cells when co-transplanted with CD133(+) hematopoietic stem cells at a ratio of 8:1 in immunodeficient NOD/SCID-IL2Rgamma(null) mice. They induced a 10.4-fold increase in the number of T cells, a 2.5-fold increase in the number of NK cells, and a 3.6-fold increase in the number of B cells, indicating a major qualitative difference between these two mesenchymal stromal cell populations. Conclusions Our results indicate that CD271 antigen provides a versatile marker for prospective isolation and expansion of multipotent mesenchymal stromal cells with immunosuppressive and lymphohematopoietic engraftment-promoting properties. The co-transplantation of such cells together with hematopoietic stem cells in patients with hematologic malignancies may prove valuable in the prevention of impaired/delayed T-cell recovery and graft-versus-host disease.