miR‐21 Modulates the Immunoregulatory Function of Bone Marrow Mesenchymal Stem Cells Through the PTEN/Akt/TGF‐β1 Pathway

Abstract microRNAs (miRNAs) act as regulatory signals for maintaining stemness, self-renewal, and differentiation of mesenchymal stem cells (MSCs), but whether miRNAs modulate the immunoregulatory function of MSCs remains largely unknown. Here, we show that miR-21 negatively regulates the activity of immunoregulatory cytokine transforming growth factor-β1 (TGF-β1) in MSCs. Consistently, bone marrow MSCs (BMMSCs) from miR-21(-/-) mice show enhanced immunosuppressive function by more TGF-β1 secretion and induce more CD4(+) Foxp3(+) regulatory T cells compared with wild-type BMMSCs in vitro, which anti-TGF-β1 antibody abrogates. Mechanistically, miR-21 inhibits TGF-β1 expression by targeting phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in BMMSCs. Downstream of PTEN, miR-21 promotes activation of Akt, and consequently increases activation of NF-κB pathway. Importantly, adoptive transfer of miR-21(-/-) BMMSCs into mice with experimental colitis more effectively ameliorates colonic inflammation in a TGF-β1-dependent manner. Thus, these findings indicate a previously uncovered mechanism of miR-21 control immunoregulatory function of BMMSCs through TGF-β1 inhibition. Stem Cells 2015;33:3281-3290.