Rescue from Pseudomonas aeruginosa Airway Infection via Stem Cell Transplantation.
Animals
Cystic Fibrosis
/ genetics
Cystic Fibrosis Transmembrane Conductance Regulator
/ genetics
Epithelial Cells
/ microbiology
Hematopoietic Stem Cell Transplantation
/ methods
Humans
Lung
/ microbiology
Macrophages
/ immunology
Mice
Mutation
Pseudomonas Infections
/ complications
Pseudomonas aeruginosa
/ isolation & purification
Pseudomonas aeruginosa
airway macrophages
chronic lung infection
cystic fibrosis
hematopoietic stem cell transplantation
mouse model
non-epithelial cells
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
03 03 2021
03 03 2021
Historique:
received:
20
05
2020
revised:
21
07
2020
accepted:
29
11
2020
pubmed:
7
12
2020
medline:
19
11
2021
entrez:
6
12
2020
Statut:
ppublish
Résumé
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which lead to impaired ion transport in epithelial cells. Although lung failure due to chronic infection is the major comorbidity in individuals with cystic fibrosis, the role of CFTR in non-epithelial cells has not been definitively resolved. Given the important role of host defense cells, we evaluated the Cftr deficiency in pulmonary immune cells by hematopoietic stem cell transplantation in cystic fibrosis mice. We transplanted healthy bone marrow stem cells and could reveal a stable chimerism of wild-type cells in peripheral blood. The outcome of stem cell transplantation and the impact of healthy immune cells were evaluated in acute Pseudomonas aeruginosa airway infection. In this study, mice transplanted with wild-type cells displayed better survival, lower lung bacterial numbers, and a milder disease course. This improved physiology of infected mice correlated with successful intrapulmonary engraftment of graft-derived alveolar macrophages, as seen by immunofluorescence microscopy and flow cytometry of graft-specific leucocyte surface marker CD45 and macrophage marker CD68. Given the beneficial effect of hematopoietic stem cell transplantation and stable engraftment of monocyte-derived CD68-positive macrophages, we conclude that replacement of mutant Cftr macrophages attenuates airway infection in cystic fibrosis mice.
Identifiants
pubmed: 33279724
pii: S1525-0016(20)30660-2
doi: 10.1016/j.ymthe.2020.12.003
pmc: PMC7935663
pii:
doi:
Substances chimiques
CFTR protein, human
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1324-1334Informations de copyright
Copyright © 2020. Published by Elsevier Inc.
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