Mesenchymal stem cells correct inappropriate epithelial-mesenchyme relation in pulmonary fibrosis using stanniocalcin-1.
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.
Department of Respiratory Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Manabu
M
Ono
1] Department of Respiratory Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan [2] Department of Occupational Health, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Shinya
S
Ohkouchi
1] Department of Respiratory Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan [2] Department of Hematology and Rheumatology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Masahiko
M
Kanehira
Department of Respiratory Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Naoki
N
Tode
Department of Respiratory Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Makoto
M
Kobayashi
Pulmonary Center, Tohoku Pharmaceutical University Hospital, Sendai, Japan.
Masahito
M
Ebina
Japan Anti-tuberculosis Association, Tokyo, Japan.
Toshihiro
T
Nukiwa
Department of Occupational Health, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Toshiya
T
Irokawa
Department of Occupational Health, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Hiromasa
H
Ogawa
Department of Environmental Health Sciences and Molecular Toxicology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Takaaki
T
Akaike
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Yoshinori
Y
Okada
Department of Occupational Health, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Hajime
H
Kurosawa
Department of Respiratory Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Toshiaki
T
Kikuchi
Department of Respiratory Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Masakazu
M
Ichinose
D000818:Animals; D001761:Bleomycin; D002450:Cell Communication; D003587:Cytomegalovirus / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D000071246:Uncoupling Protein 2
D006023:Glycoproteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D053773:Transforming Growth Factor beta1; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D001761:Bleomycin; C051795:teleocalcin