title: Microencapsulation of Lefty-secreting engineered cells for pulmonary fibrosis therapy in mice.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor-β signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined whether Lefty A can attenuate bleomycin (BLM)-induced pulmonary fibrosis in vivo based on a novel therapeutic strategy where human embryonic kidney 293 (HEK293) cells are genetically engineered with the Lefty A-associatedGFPgene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had 1 wk earlier been intratracheally administered BLM to induce pulmonary fibrosis. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor and collagen type I mRNA, lessened the morphological fibrotic effects induced by BLM, and increased the expression of matrix metalloproteinase-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate pulmonary fibrosis in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Hongge
authors.initials: H
authors.lastname: Ma
authors.affiliation: Bio-X Center, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Shupei
authors.initials: S
authors.lastname: Qiao
authors.affiliation: Bio-X Center, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Zeli
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, China; and.
authors.forename: Shuai
authors.initials: S
authors.lastname: Geng
authors.affiliation: Bio-X Center, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Bio-X Center, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Hou
authors.affiliation: Bio-X Center, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Tian
authors.affiliation: Division of Biomedical Engineering, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Xiongbiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, China; yaolifen_2015@sina.com.
authors.forename: Lifen
authors.initials: L
authors.lastname: Yao
mesh_terms: D000818:Animals; D060846:Cell Engineering; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004339:Drug Compounding; D005822:Genetic Vectors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D055458:Left-Right Determination Factors / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008813:Mice, Inbred ICR; D008863:Microspheres; D011658:Pulmonary Fibrosis / Q000473:pathology* / Q000628:therapy*; D012190:Retroviridae / Q000378:metabolism
chemical_list: D055458:Left-Right Determination Factors; D055513:Connective Tissue Growth Factor; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Lefty A; idiopathic pulmonary fibrosis; matrix metalloproteinase-9; microencapsulated cells