title: Partial Restoration of CFTR Function in cftr-Null Mice following Targeted Cell Replacement Therapy.
abstract: Cystic fibrosis (CF) is a fatal recessive genetic disorder caused by a mutation in the gene encoding CF transmembrane conductance regulator (CFTR) protein. Alteration in CFTR leads to thick airway mucus and bacterial infection. Cell therapy has been proposed for CFTR restoration, but efficacy has been limited by low engraftment levels. In our previous studies, we have shown that using a pre-conditioning regimen in combination with optimization of cell number and time of delivery, we could obtain greater bone marrow cell (BMC) retention in the lung. Here, we found that optimized delivery of wild-type (WT) BMC contributed to apical CFTR expression in airway epithelium and restoration of select ceramide species and fatty acids in CFTR-/-mice. Importantly, WT BMC delivery delayed Pseudomonas aeruginosa lung infection and increased survival of CFTR-/-recipients. Only WT BMCs had a beneficial effect beyond 6 months, suggesting a dual mechanism of BMC benefit: a non-specific effect early after cell delivery, possibly due to the recruitment of macrophages and neutrophils, and a late beneficial effect dependent on long-term CFTR expression. Taken together, our results suggest that BMC can improve overall lung function and may have potential therapeutic benefit for the treatment of CF.
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Pascal
authors.initials: P
authors.lastname: Duchesneau
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Rickvinder
authors.initials: R
authors.lastname: Besla
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Mathieu F
authors.initials: MF
authors.lastname: Derouet
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Guo
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Golnaz
authors.initials: G
authors.lastname: Karoubi
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Silberberg
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Wong
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, Toronto General Hospital Research Institute, University of Toronto, Toronto, ON M5G 2C4, Canada. Electronic address: tom.waddell@uhn.on.ca.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D064987:Cell- and Tissue-Based Therapy; D002518:Ceramides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D016207:Cytokines; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism
chemical_list: D002518:Ceramides; D016207:Cytokines; D005227:Fatty Acids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; cell therapy; lung regeneration