title: 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.
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.affiliation: Laboratory of Tissue Regeneration and Immunology and Department of Periodontics.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Signaling and Stem Cell Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.
authors.forename: Junji
authors.initials: J
authors.lastname: Xu
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.
authors.forename: Luyuan
authors.initials: L
authors.lastname: Jin
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.
authors.forename: Lei
authors.initials: L
authors.lastname: Hu
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Chen
authors.affiliation: Molecular Laboratory for Gene Therapy and Tooth Regeneration.|Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medical Sciences, Beijing, China.
authors.forename: Songlin
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Immunoregulation; Mesenchymal stem cells; PTEN; Transforming growth factor-β1; miR-21