title: Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1β-Primed Mesenchymal Stem Cells Against Sepsis.
abstract: Improving the immunomodulatory efficacy of mesenchymal stem cells (MSCs) through pretreatment with pro-inflammatory cytokines is an evolving field of investigation. However, the underlying mechanisms have not been fully clarified. Here, we pretreated human umbilical cord-derived MSCs with interleukin-1β (IL-1β) and evaluated their therapeutic effects in a cecal ligation and puncture-induced sepsis model. We found that systemic administration of IL-1β-pretreated MSCs (βMSCs) ameliorated the symptoms of murine sepsis more effectively and increased the survival rate compared with naïve MSCs. Furthermore, βMSCs could more effectively induce macrophage polarization toward an anti-inflammatory M2 phenotype through the paracrine activity. Mechanistically, we demonstrated that βMSC-derived exosomes contributed to the enhanced immunomodulatory properties of βMSCs both in vitro and in vivo. Importantly, we found that miR-146a, a well-known anti-inflammatory microRNA, was strongly upregulated by IL-1β stimulation and selectively packaged into exosomes. This exosomal miR-146a was transferred to macrophages, resulted in M2 polarization, and finally led to increased survival in septic mice. In contrast, inhibition of miR-146a through transfection with miR-146a inhibitors partially negated the immunomodulatory properties of βMSC-derived exosomes. Taken together, IL-1β pretreatment effectively enhanced the immunomodulatory properties of MSCs partially through exosome-mediated transfer of miR-146a. Therefore, we believe that IL-1β pretreatment may provide a new modality for better therapeutic application of MSCs in inflammatory disorders. Stem Cells 2017;35:1208-1221.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.|Central Laboratory of Stomatology, Nanjing Stomatology Hospital, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Song
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.|Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Huan
authors.initials: H
authors.lastname: Dou
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.|Department of Obstetrics and Gynecology, The Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, China.
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.|Department of Obstetrics and Gynecology, The Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Ji
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ding
authors.affiliation: Central Laboratory of Stomatology, Nanjing Stomatology Hospital, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Ni
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, People's Republic of China.|Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, People's Republic of China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000187:drug effects; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects; D010641:Phenotype; D018805:Sepsis / Q000517:prevention & control / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D053583:Interleukin-1beta; C542542:MIRN146 microRNA, human; D035683:MicroRNAs
keywords: Exosome; IL-1β; Macrophage polarization; Mesenchymal stem cells; Sepsis; miR-146a