Hepatocyte growth factor secreted by bone marrow stem cell reduce ER stress and improves repair in alveolar epithelial II cells.
Idiopathic Pulmonary Fibrosis (IPF) is a progressive, irreversible lung disease with complex pathophysiology. Evidence of endoplasmic reticulum (ER) stress has been reported in alveolar epithelial cells (AEC) in IPF patients. Secreted mediators from bone marrow stem cells (BMSC-cm) have regenerative properties. In this study we investigate the beneficial effects of BMSC-cm on ER stress response in primary AEC and ER stressed A549 cells. We hypothesize that BMSC-cm reduces ER stress. Primary AEC isolated from IPF patients were treated with BMSC-cm. To induce ER stress A549 cells were incubated with Tunicamycin or Thapsigargin and treated with BMSC-cm, or control media. Primary IPF-AEC had high Grp78 and CHOP gene expression, which was lowered after BMSC-cm treatment. Similar results were observed in ER stressed A549 cells. Alveolar epithelial repair increased in presence of BMSC-cm in ER stressed A549 cells. Hepatocyte growth factor (HGF) was detected in biologically relevant levels in BMSC-cm. Neutralization of HGF in BMSC-cm attenuated the beneficial effects of BMSC-cm including synthesis of surfactant protein C (SP-C) in primary AEC, indicating a crucial role of HGF in ER homeostasis and alveolar epithelial repair. Our data suggest that BMSC-cm may be a potential therapeutic option for treating pulmonary fibrosis.
Department of Pulmonary Medicine, University Hospital Bern, Switzerland.|Department of Clinical Research University of Bern, Switzerland.
Izabela
I
Nita
Pulmonary Cell Research, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
Katrin
K
Hostettler
Department of Pulmonary Medicine, University Hospital Bern, Switzerland.|Department of Clinical Research University of Bern, Switzerland.|Graduate school of Biomedical science, University of Bern, Bern, Switzerland.
Luca
L
Tamo
Department of Clinical Research University of Bern, Switzerland.|Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
Michaela
M
Medová
Department of Clinical Research University of Bern, Switzerland.|Graduate school of Biomedical science, University of Bern, Bern, Switzerland.|Department of Hematology, University Hospital Bern, Bern, Switzerland.
Giuseppe
G
Bombaci
Pulmonary Cell Research, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
Jun
J
Zhong
Department of Clinical Research University of Bern, Switzerland.|Department of Hematology, University Hospital Bern, Bern, Switzerland.
Ramanjaneyulu
R
Allam
Department of Clinical Research University of Bern, Switzerland.|Department of Radiation Oncology, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
Yitzhak
Y
Zimmer
Pulmonary Cell Research, Department of Biomedicine, University and University Hospital Basel, Basel, Switzerland.
Michael
M
Roth
Department of Pulmonary Medicine, University Hospital Bern, Switzerland.|Department of Clinical Research University of Bern, Switzerland.
Thomas
T
Geiser
Department of Pulmonary Medicine, University Hospital Bern, Switzerland.|Department of Clinical Research University of Bern, Switzerland.
Amiq
A
Gazdhar
D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019284:Thapsigargin / Q000633:toxicity; D014415:Tunicamycin / Q000633:toxicity
D017077:Culture Media, Conditioned; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D014415:Tunicamycin; D017228:Hepatocyte Growth Factor; D019284:Thapsigargin