RRC ID 45363
Author Ono M, Ohkouchi S, Kanehira M, Tode N, Kobayashi M, Ebina M, Nukiwa T, Irokawa T, Ogawa H, Akaike T, Okada Y, Kurosawa H, Kikuchi T, Ichinose M.
Title Mesenchymal stem cells correct inappropriate epithelial-mesenchyme relation in pulmonary fibrosis using stanniocalcin-1.
Journal Mol. Ther.
Abstract Current hypotheses suggest that aberrant wound healing has a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). In these hypotheses, continuous TGF-β1 secretion by alveolar epithelial cells (AECs) in abnormal wound healing has a critical role in promoting fibroblast differentiation into myofibroblasts. Mesenchymal stem cells (MSCs) home to the injury site and reduce fibrosis by secreting multifunctional antifibrotic humoral factors in IPF. In this study, we show that MSCs can correct the inadequate-communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion in a bleomycin-induced IPF model. Inhalation of recombinant STC1 shows the same effects as the injection of MSCs. Using STC1 plasmid, it was possible to enhance the ability of MSCs to ameliorate the fibrosis. MSCs secrete large amounts of STC1 in response to TGF-β1 in comparison to AECs and fibroblasts. The antifibrotic effects of STC1 include reducing oxidative stress, endoplasmic reticulum (ER) stress, and TGF-β1 production in AECs. The STC1 effects can be controlled by blocking uncoupling protein 2 (UCP2) and the secretion is affected by the PI3/AKT/mTORC1 inhibitors. Our findings suggest that STC1 tends to correct the inappropriate epithelial-mesenchymal relationships and that STC1 plasmid transfected to MSCs or STC1 inhalation could become promising treatments for IPF.
Volume 23(3)
Pages 549-60
Published 2015-3
DOI 10.1038/mt.2014.217
PII S1525-0016(16)30067-3
PMID 25373521
PMC PMC4351453
MeSH Animals Bleomycin Cell Communication Cytomegalovirus / genetics Endoplasmic Reticulum Stress / genetics Epithelial Cells / metabolism* Epithelial Cells / pathology Female Fibroblasts / metabolism* Fibroblasts / pathology Gene Expression Regulation Genetic Vectors Glycoproteins / genetics Glycoproteins / metabolism* Humans Idiopathic Pulmonary Fibrosis / chemically induced Idiopathic Pulmonary Fibrosis / genetics* Idiopathic Pulmonary Fibrosis / metabolism Idiopathic Pulmonary Fibrosis / pathology Ion Channels / genetics Ion Channels / metabolism Mesenchymal Stem Cells / metabolism* Mesenchymal Stem Cells / pathology Mice, Inbred C57BL Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism Oxidative Stress Plasmids / chemistry Plasmids / metabolism Pulmonary Alveoli / metabolism* Pulmonary Alveoli / pathology Signal Transduction Transfection Transforming Growth Factor beta1 / genetics Transforming Growth Factor beta1 / metabolism Uncoupling Protein 2
IF 7.008
Times Cited 11
Human and Animal Cells