Epithelial disruption: A new paradigm enabling human airway stem cell transplantation

Nigel Farrow, Patricia Cmielewski, Martin Donnelley, Nathan Rout-Pitt, Yuben Moodley, Ivan Bertoncello, David Parsons

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Airway disease is a primary cause of morbidity and early mortality for patients with cystic fibrosis (CF). Cell transplantation therapy has proven successful for treating immune disorders and may have the potential to correct the airway disease phenotype associated with CF. Since in vivo cell delivery into unconditioned mouse airways leads to inefficient engraftment, we hypothesised that disrupting the epithelial cell layer using the agent polidocanol (PDOC) would facilitate effective transplantation of cultured stem cells in mouse nasal airways. Methods: In this study, 4 μL of 2% PDOC in phosphate-buffered saline was administered to the nasal airway of mice to disrupt the epithelium. At 2 or 24 h after PDOC treatment, two types of reporter gene-expressing cells were transplanted into the animals: luciferase-transduced human airway basal cells (hABC-Luc) or luciferase-transduced human amnion epithelial cells (hAEC-Luc). Bioluminescence imaging was used to assess the presence of transplanted luciferase-expressing cells over time. Data were evaluated by using two-way analysis of variance with Sidak's multiple comparison. Results: Successful transplantation was observed when hABCs were delivered 2 h after PDOC but was absent when transplantation was performed 24 h after PDOC, suggesting that a greater competitive advantage for the donor cells is present at the earlier time point. The lack of transplantation of hAECs 24 h after PDOC supports the importance of choosing the correct timing and cell type to facilitate transplantation. Conclusions: These studies into factors that may enable successful airway transplantation of human stem cells showed that extended functioning cell presence is feasible and further supports the development of methods that alter normal epithelial layer integrity. With improvements in efficacy, manipulating the airway epithelium to make it permissive towards cell transplantation may provide another option for safe and effective correction of CF transmembrane conductance regulator function in CF airways.

Original languageEnglish
Article number153
JournalStem Cell Research and Therapy
Volume9
Issue number1
DOIs
Publication statusPublished - 13 Jun 2018

Fingerprint

Stem Cell Transplantation
Stem cells
Transplantation
Luciferases
Cystic Fibrosis
Cell Transplantation
Nose
Epithelium
Epithelial Cells
Cystic Fibrosis Transmembrane Conductance Regulator
Amnion
Immune System Diseases
Bioluminescence
Cell- and Tissue-Based Therapy
Reporter Genes
polidocanol
Cultured Cells
Analysis of Variance
Analysis of variance (ANOVA)
Phosphates

Cite this

Farrow, N., Cmielewski, P., Donnelley, M., Rout-Pitt, N., Moodley, Y., Bertoncello, I., & Parsons, D. (2018). Epithelial disruption: A new paradigm enabling human airway stem cell transplantation. Stem Cell Research and Therapy, 9(1), [153]. https://doi.org/10.1186/s13287-018-0911-4
Farrow, Nigel ; Cmielewski, Patricia ; Donnelley, Martin ; Rout-Pitt, Nathan ; Moodley, Yuben ; Bertoncello, Ivan ; Parsons, David. / Epithelial disruption : A new paradigm enabling human airway stem cell transplantation. In: Stem Cell Research and Therapy. 2018 ; Vol. 9, No. 1.
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Farrow, N, Cmielewski, P, Donnelley, M, Rout-Pitt, N, Moodley, Y, Bertoncello, I & Parsons, D 2018, 'Epithelial disruption: A new paradigm enabling human airway stem cell transplantation' Stem Cell Research and Therapy, vol. 9, no. 1, 153. https://doi.org/10.1186/s13287-018-0911-4

Epithelial disruption : A new paradigm enabling human airway stem cell transplantation. / Farrow, Nigel; Cmielewski, Patricia; Donnelley, Martin; Rout-Pitt, Nathan; Moodley, Yuben; Bertoncello, Ivan; Parsons, David.

In: Stem Cell Research and Therapy, Vol. 9, No. 1, 153, 13.06.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epithelial disruption

T2 - A new paradigm enabling human airway stem cell transplantation

AU - Farrow, Nigel

AU - Cmielewski, Patricia

AU - Donnelley, Martin

AU - Rout-Pitt, Nathan

AU - Moodley, Yuben

AU - Bertoncello, Ivan

AU - Parsons, David

PY - 2018/6/13

Y1 - 2018/6/13

N2 - Background: Airway disease is a primary cause of morbidity and early mortality for patients with cystic fibrosis (CF). Cell transplantation therapy has proven successful for treating immune disorders and may have the potential to correct the airway disease phenotype associated with CF. Since in vivo cell delivery into unconditioned mouse airways leads to inefficient engraftment, we hypothesised that disrupting the epithelial cell layer using the agent polidocanol (PDOC) would facilitate effective transplantation of cultured stem cells in mouse nasal airways. Methods: In this study, 4 μL of 2% PDOC in phosphate-buffered saline was administered to the nasal airway of mice to disrupt the epithelium. At 2 or 24 h after PDOC treatment, two types of reporter gene-expressing cells were transplanted into the animals: luciferase-transduced human airway basal cells (hABC-Luc) or luciferase-transduced human amnion epithelial cells (hAEC-Luc). Bioluminescence imaging was used to assess the presence of transplanted luciferase-expressing cells over time. Data were evaluated by using two-way analysis of variance with Sidak's multiple comparison. Results: Successful transplantation was observed when hABCs were delivered 2 h after PDOC but was absent when transplantation was performed 24 h after PDOC, suggesting that a greater competitive advantage for the donor cells is present at the earlier time point. The lack of transplantation of hAECs 24 h after PDOC supports the importance of choosing the correct timing and cell type to facilitate transplantation. Conclusions: These studies into factors that may enable successful airway transplantation of human stem cells showed that extended functioning cell presence is feasible and further supports the development of methods that alter normal epithelial layer integrity. With improvements in efficacy, manipulating the airway epithelium to make it permissive towards cell transplantation may provide another option for safe and effective correction of CF transmembrane conductance regulator function in CF airways.

AB - Background: Airway disease is a primary cause of morbidity and early mortality for patients with cystic fibrosis (CF). Cell transplantation therapy has proven successful for treating immune disorders and may have the potential to correct the airway disease phenotype associated with CF. Since in vivo cell delivery into unconditioned mouse airways leads to inefficient engraftment, we hypothesised that disrupting the epithelial cell layer using the agent polidocanol (PDOC) would facilitate effective transplantation of cultured stem cells in mouse nasal airways. Methods: In this study, 4 μL of 2% PDOC in phosphate-buffered saline was administered to the nasal airway of mice to disrupt the epithelium. At 2 or 24 h after PDOC treatment, two types of reporter gene-expressing cells were transplanted into the animals: luciferase-transduced human airway basal cells (hABC-Luc) or luciferase-transduced human amnion epithelial cells (hAEC-Luc). Bioluminescence imaging was used to assess the presence of transplanted luciferase-expressing cells over time. Data were evaluated by using two-way analysis of variance with Sidak's multiple comparison. Results: Successful transplantation was observed when hABCs were delivered 2 h after PDOC but was absent when transplantation was performed 24 h after PDOC, suggesting that a greater competitive advantage for the donor cells is present at the earlier time point. The lack of transplantation of hAECs 24 h after PDOC supports the importance of choosing the correct timing and cell type to facilitate transplantation. Conclusions: These studies into factors that may enable successful airway transplantation of human stem cells showed that extended functioning cell presence is feasible and further supports the development of methods that alter normal epithelial layer integrity. With improvements in efficacy, manipulating the airway epithelium to make it permissive towards cell transplantation may provide another option for safe and effective correction of CF transmembrane conductance regulator function in CF airways.

KW - Airways

KW - Gene therapy

KW - Stem cells

KW - Transplantation

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