title: Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents With Bleomycin-Induced Pulmonary Fibrosis.
abstract: Lung diseases are devastating conditions and ranked as one of the top five causes of mortality worldwide according to the World Health Organization. Stem cell therapy is a promising strategy for lung regeneration. Previous animal and clinical studies have focused on the use of mesenchymal stem cells (from other parts of the body) for lung regenerative therapies. We report a rapid and robust method to generate therapeutic resident lung progenitors from adult lung tissues. Outgrowth cells from healthy lung tissue explants are self-aggregated into three-dimensional lung spheroids in a suspension culture. Without antigenic sorting, the lung spheroids recapitulate the stem cell niche and contain a natural mixture of lung stem cells and supporting cells. In vitro, lung spheroid cells can be expanded to a large quantity and can form alveoli-like structures and acquire mature lung epithelial phenotypes. In severe combined immunodeficiency mice with bleomycin-induced pulmonary fibrosis, intravenous injection of human lung spheroid cells inhibited apoptosis, fibrosis, and infiltration but promoted angiogenesis. In a syngeneic rat model of pulmonary fibrosis, lung spheroid cells outperformed adipose-derived mesenchymal stem cells in reducing fibrotic thickening and infiltration. Previously, lung spheroid cells (the spheroid model) had only been used to study lung cancer cells. Our data suggest that lung spheroids and lung spheroid cells from healthy lung tissues are excellent sources of regenerative lung cells for therapeutic lung regeneration.
  
  
  CONCLUSIONS
  The results from the present study will lead to future human clinical trials using lung stem cell therapies to treat various incurable lung diseases, including pulmonary fibrosis. The data presented here also provide fundamental knowledge regarding how injected stem cells mediate lung repair in pulmonary fibrosis.
authors.affiliation: Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, and North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Henry
authors.affiliation: Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, and North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Jhon
authors.initials: J
authors.lastname: Cores
authors.affiliation: Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: M Taylor
authors.initials: MT
authors.lastname: Hensley
authors.affiliation: Department of Biology, North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Shirena
authors.initials: S
authors.lastname: Anthony
authors.affiliation: Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, and North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Vandergriff
authors.affiliation: Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: James B M
authors.initials: JB
authors.lastname: de Andrade
authors.affiliation: Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Allen
authors.affiliation: Division of Cardiothoracic Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Caranasos
authors.affiliation: Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Lobo
authors.affiliation: Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, and North Carolina State University, Raleigh, North Carolina, USA ke_cheng@ncsu.edu ke_cheng@unc.edu.
authors.forename: Ke
authors.initials: K
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D012038:Regeneration; D018874:Spheroids, Cellular / Q000378:metabolism / Q000637:transplantation*
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin
keywords: Adult lung stem cells; Mesenchymal stem cells; Pulmonary fibrosis; Spheroid cell culture