Abstract

Mesenchymal stem cells (MSC) have been shown to elicit immunosuppressive effect on allogeneic lymphocyte response. However, MSC are heterogeneous and data on the inhibitory abilities of different MSC subsets are lacking. The Stro-1 antigen potentially defines a more pure and more primitive MSC subset

We compared the suppressive property of expanded Stro-1+ and Stro-1 MSC when add to mixed lymphocyte reactions (MLR) or to mitogen response assays. Results showed that T lymphocyte proliferation was significantly more inhibited by expanded Stro-1+ (11.0%~63.7% of maximal response) than by expanded stro-1 MSC (35.5%~106% of maximal response) (p<0.01). Results indicated that as few as 1,000 expanded Stro-1+ MSC could induce a similar inhibition of lymphocyte proliferation than 10 times more (10,000 cells) expanded Stro-1 MSC . Stro-1+ MSC was the main population responsible for T cell inhibition. The expression of genes coding for inhibitors of T-cell activation and proliferation (IL-10, LIF, IDO, TGF-b1, HGF, HLA-G), for adhesion molecules (VCAM, LFA-3), and for chemotactic factors (IL-8, SDF-1) was analysed by semi-quantitative real time RT-PCR in the Stro1+ and Stro1- MSC. Results are expressed as a fold increase in the mRNA level in expanded Stro-1+ compared to Stro-1 MSC. IL-10 (0.24 fold p=0.002) and TGF-β1 (0.43 fold, p=0.03) were down regulated in expanded Stro-1+ compared to Stro-1 MSC. LIF (106 fold, p=0.025), IDO (6130 fold, p=0.04), HGF (24 fold, p=0.01), and HLA-G (260 fold, p= 0.02) were up regulated in expanded Stro-1+ compared to Stro-1 MSC. VCAM-1 and LFA-3 were up regulated in expanded Stro-1+ compared to Stro-1 MSC (28.2 fold, p=0.03 and 298.4 fold, p=0.04 for VCAM-1 and LFA-3 respectively): IL-8 was over expressed in expanded Stro-1+ (4.9 fold, p=0.0015). There was no significant difference between expanded Stro-1+ and Stro-1 MSC for SDF-1. These results suggest that LIF, IDO, HGF, HLA-G inhibitory factors and VCAM1, LFA-3 adhesion molecules are mainly responsible for the different T cell inhibition observed between Stro-1+ and Stro-1 MSC.

These findings suggest that in clinics a Stro-1+ pre-selection of MSC might produce a more effective immunosuppression especially for the prevention and the treatment of graft versus host disease.

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