title: The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation.
abstract: Tissue-resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis, and tumor formation. Here, we define a population of resident lung MSCs (luMSCs) that function to regulate the severity of bleomycin injury via modulation of the T-cell response. Bleomycin-induced loss of these endogenous luMSCs and elicited fibrosis (pulmonary fibrosis), inflammation, and pulmonary arterial hypertension (PAH). Replacement of resident stem cells by administration of isolated luMSCs attenuated the bleomycin-associated pathology and mitigated the development of PAH. In addition, luMSC modulated a decrease in numbers of lymphocytes and granulocytes in bronchoalveolar fluid and demonstrated an inhibition of effector T-cell proliferation in vitro. Global gene expression analysis indicated that the luMSCs are a unique stromal population differing from lung fibroblasts in terms of proinflammatory mediators and profibrotic pathways. Our results demonstrate that luMSCs function to protect lung integrity after injury; however, when endogenous MSCs are lost, this function is compromised illustrating the importance of this novel population during lung injury. The definition of this population in vivo in both murine and human pulmonary tissue facilitates the development of a therapeutic strategy directed at the rescue of endogenous cells to facilitate lung repair during injury.
authors.affiliation: Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology Program, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Du
authors.initials: D
authors.lastname: Jun
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Garat
authors.forename: James
authors.initials: J
authors.lastname: West
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thorn
authors.forename: Kelsey
authors.initials: K
authors.lastname: Chow
authors.forename: Timothy
authors.initials: T
authors.lastname: Cleaver
authors.forename: Timothy
authors.initials: T
authors.lastname: Sullivan
authors.forename: Enrique C
authors.initials: EC
authors.lastname: Torchia
authors.forename: Christine
authors.initials: C
authors.lastname: Childs
authors.forename: Theodore
authors.initials: T
authors.lastname: Shade
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Tadjali
authors.forename: Abigail
authors.initials: A
authors.lastname: Lara
authors.forename: Eva
authors.initials: E
authors.lastname: Nozik-Grayck
authors.forename: Stephen
authors.initials: S
authors.lastname: Malkoski
authors.forename: Brian
authors.initials: B
authors.lastname: Sorrentino
authors.forename: Barbara
authors.initials: B
authors.lastname: Meyrick
authors.forename: Dwight
authors.initials: D
authors.lastname: Klemm
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: David H
authors.initials: DH
authors.lastname: Wagner
authors.forename: Susan M
authors.initials: SM
authors.lastname: Majka
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects* / Q000494:pharmacology; D049109:Cell Proliferation; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000473:pathology; D055370:Lung Injury; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D001761:Bleomycin