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Article ; Online: Pulmonary Ionocytes Challenge the Paradigm in Cystic Fibrosis.

Hawkins, Finn J / Kotton, Darrell N

2018 Volume 39, Issue 10, Page(s) 852–854

Abstract: Two recent studies have identified novel airway cells termed pulmonary ionocytes that express higher levels of CFTR than other airway cells express. These findings raise new questions in the evolving debate about the physiological role of CFTR in lung ... ...

Abstract	Two recent studies have identified novel airway cells termed pulmonary ionocytes that express higher levels of CFTR than other airway cells express. These findings raise new questions in the evolving debate about the physiological role of CFTR in lung epithelia and its importance in the pathogenesis of cystic fibrosis (CF).
MeSH term(s)	Cystic Fibrosis ; Cystic Fibrosis Transmembrane Conductance Regulator ; Epithelium ; Humans ; Lung
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2018-09-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2018.08.005
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Zs.A 1513: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Hospital-level variation in practices and outcomes for patients with severe acute exacerbations of idiopathic pulmonary fibrosis: a retrospective multicentre cohort study.

Shankar, Divya A / Walkey, Allan J / Hawkins, Finn J / Bosch, Nicholas A / Peterson, Daniel / Law, Anica C

BMJ open respiratory research

2023 Volume 10, Issue 1

Abstract: Background: In the absence of evidence-based strategies to improve patient outcomes, the management of patients with severe idiopathic pulmonary fibrosis (IPF) exacerbations may vary widely across centres. We assessed between-hospital variation in ... ...

Abstract	Background: In the absence of evidence-based strategies to improve patient outcomes, the management of patients with severe idiopathic pulmonary fibrosis (IPF) exacerbations may vary widely across centres. We assessed between-hospital variation in practices and mortality for patients with severe IPF exacerbations. Methods: Using the Premier Healthcare Database from 1 October 2015 to 31 December 2020, we identified patients admitted to intensive care unit (ICU) or intermediate care unit with an IPF exacerbation. We assessed idiosyncratic, between-hospital variation in ICU practices (invasive mechanical ventilation (IMV), non-invasive mechanical ventilation (NIMV), corticosteroid use, and immunosuppressive and/or antioxidant use) and hospital mortality by determining median risk-adjusted hospital rates and intraclass correlation coefficients (ICCs) from hierarchical multivariable regression models. A priori, an ICC>15% was deemed 'high variation'. Results: We identified 5256 critically ill patients with a severe IPF exacerbation at 385 US hospitals. Hospital median risk-adjusted rates of practices were: IMV (14% (IQR: 8.3%-26%)), NIMV (42% (31%-54%)), corticosteroid use (89% (84%-93%)), and immunosuppressive and/or antioxidant use (3.3% (1.9%-5.8%)). Model ICCs were: IMV (19% (95% CI: 18% to 21%)), NIMV (15% (13% to 16%)), corticosteroid use (9.8% (8.3% to 11%)), and immunosuppressive and/or antioxidant use (8.5% (7.1% to 9.9%)). The median risk-adjusted hospital mortality was 16% (IQR: 11%-24%) with an ICC of 7.5% (95% CI: 6.2% to 8.9%). Interpretation: We observed high variation in the use of IMV and NIMV, and less variation in corticosteroid and immunosuppressant and/or antioxidant use among patients hospitalised with severe IPF exacerbations. Further research is needed to guide the decisions surrounding initiation of IMV and role of NIMV and to understand the effectiveness of corticosteroids among patients with severe IPF exacerbations.
MeSH term(s)	Humans ; Cohort Studies ; Antioxidants ; Idiopathic Pulmonary Fibrosis/therapy ; Respiration, Artificial ; Hospitals
Chemical Substances	Antioxidants
Language	English
Publishing date	2023-04-20
Publishing country	England
Document type	Multicenter Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2736454-9
ISSN	2052-4439 ; 2052-4439
ISSN (online)	2052-4439
ISSN	2052-4439
DOI	10.1136/bmjresp-2022-001593
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Article ; Online: Differentiation of human pluripotent stem cells into functional airway basal stem cells.

Suzuki, Shingo / Hawkins, Finn J / Barillà, Cristina / Beermann, Mary Lou / Kotton, Darrell N / Davis, Brian R

STAR protocols

2021 Volume 2, Issue 3, Page(s) 100683

Abstract: Airway basal cells play an essential role in the maintenance of the airway epithelium. Here, we provide a detailed directed differentiation protocol to generate ''induced basal cells (iBCs)'' from human pluripotent stem cells. iBCs recapitulate ... ...

Abstract	Airway basal cells play an essential role in the maintenance of the airway epithelium. Here, we provide a detailed directed differentiation protocol to generate ''induced basal cells (iBCs)'' from human pluripotent stem cells. iBCs recapitulate biological and functional properties of airway basal cells including mucociliary differentiation
MeSH term(s)	Cell Culture Techniques/methods ; Cell Differentiation/physiology ; Cells, Cultured ; Endoderm/cytology ; Epithelial Cells/cytology ; Epithelium/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology ; Lung/cytology ; Organoids/cytology ; Pluripotent Stem Cells/cytology ; Respiratory System/cytology ; Tissue Engineering/methods ; Trachea/cytology
Language	English
Publishing date	2021-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2021.100683
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Article: Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy.

Brody, Steven L / Pan, Jiehong / Huang, Tao / Xu, Jian / Xu, Huihui / Koenitizer, Jeffrey / Brennan, Steven K / Nanjundappa, Rashmi / Saba, Thomas G / Berical, Andrew / Hawkins, Finn J / Wang, Xiangli / Zhang, Rui / Mahjoub, Moe R / Horani, Amjad / Dutcher, Susan K

bioRxiv : the preprint server for biology

2024

Abstract: Motile cilia have essential cellular functions in development, reproduction, and homeostasis. Genetic causes for motile ciliopathies have been identified, but the consequences on cellular functions beyond impaired motility remain unknown. Variants ... ...

Abstract	Motile cilia have essential cellular functions in development, reproduction, and homeostasis. Genetic causes for motile ciliopathies have been identified, but the consequences on cellular functions beyond impaired motility remain unknown. Variants in
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.20.585965
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Article ; Online: Viral airway injury promotes cell engraftment in an in vitro model of cystic fibrosis cell therapy.

Lee, Rhianna E / Mascenik, Teresa M / Major, Sidra C / Galiger, Jacob R / Bulik-Sullivan, Emily / Siesser, Priscila F / Lewis, Catherine A / Bear, James E / Le Suer, Jake A / Hawkins, Finn J / Pickles, Raymond J / Randell, Scott H

American journal of physiology. Lung cellular and molecular physiology

2023 Volume 326, Issue 3, Page(s) L226–L238

Abstract: Cell therapy is a potential treatment for cystic fibrosis (CF). However, cell engraftment into the airway epithelium is challenging. Here, we model cell engraftment in vitro using the air-liquid interface (ALI) culture system by injuring well- ... ...

Abstract	Cell therapy is a potential treatment for cystic fibrosis (CF). However, cell engraftment into the airway epithelium is challenging. Here, we model cell engraftment in vitro using the air-liquid interface (ALI) culture system by injuring well-differentiated CF ALI cultures and delivering non-CF cells at the time of peak injury. Engraftment efficiency was quantified by measuring chimerism by droplet digital PCR and functional ion transport in Ussing chambers. Using this model, we found that human bronchial epithelial cells (HBECs) engraft more efficiently when they are cultured by conditionally reprogrammed cell (CRC) culture methods. Cell engraftment into the airway epithelium requires airway injury, but the extent of injury needed is unknown. We compared three injury models and determined that severe injury with partial epithelial denudation facilitates long-term cell engraftment and functional CFTR recovery up to 20% of wildtype function. The airway epithelium promptly regenerates in response to injury, creating competition for space and posing a barrier to effective engraftment. We examined competition dynamics by time-lapse confocal imaging and found that delivered cells accelerate airway regeneration by incorporating into the epithelium. Irradiating the repairing epithelium granted engrafting cells a competitive advantage by diminishing resident stem cell proliferation. Intentionally, causing severe injury to the lungs of people with CF would be dangerous. However, naturally occurring events like viral infection can induce similar epithelial damage with patches of denuded epithelium. We found that viral preconditioning promoted effective engraftment of cells primed for viral resistance.
MeSH term(s)	Humans ; Cystic Fibrosis/therapy ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Epithelium ; Epithelial Cells ; Cell- and Tissue-Based Therapy ; Virus Diseases ; Cells, Cultured
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2023-12-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00421.2022
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Zs.A 2749: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Airway stem cell reconstitution by the transplantation of primary or pluripotent stem cell-derived basal cells.

Ma, Liang / Thapa, Bibek R / Le Suer, Jake A / Tilston-Lünel, Andrew / Herriges, Michael J / Berical, Andrew / Beermann, Mary Lou / Wang, Feiya / Bawa, Pushpinder S / Kohn, Anat / Ysasi, Alexandra B / Kiyokawa, Hirofumi / Matte, Taylor M / Randell, Scott H / Varelas, Xaralabos / Hawkins, Finn J / Kotton, Darrell N

Cell stem cell

2023 Volume 30, Issue 9, Page(s) 1199–1216.e7

Abstract: Life-long reconstitution of a tissue's resident stem cell compartment with engrafted cells has the potential to durably replenish organ function. Here, we demonstrate the engraftment of the airway epithelial stem cell compartment via intra-airway ... ...

Abstract	Life-long reconstitution of a tissue's resident stem cell compartment with engrafted cells has the potential to durably replenish organ function. Here, we demonstrate the engraftment of the airway epithelial stem cell compartment via intra-airway transplantation of mouse or human primary and pluripotent stem cell (PSC)-derived airway basal cells (BCs). Murine primary or PSC-derived BCs transplanted into polidocanol-injured syngeneic recipients give rise for at least two years to progeny that stably display the morphologic, molecular, and functional phenotypes of airway epithelia. The engrafted basal-like cells retain extensive self-renewal potential, evident by the capacity to reconstitute the tracheal epithelium through seven generations of secondary transplantation. Using the same approach, human primary or PSC-derived BCs transplanted into NOD scid gamma (NSG) recipient mice similarly display multilineage airway epithelial differentiation in vivo. Our results may provide a step toward potential future syngeneic cell-based therapy for patients with diseases resulting from airway epithelial cell damage or dysfunction.
MeSH term(s)	Humans ; Animals ; Mice ; Pluripotent Stem Cells ; Cell- and Tissue-Based Therapy ; Epithelial Cells ; Epithelium ; Mice, Inbred NOD ; Mice, SCID
Language	English
Publishing date	2023-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2023.07.014
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Zs.A 6589: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: De Novo

Wang, Ruobing / Simone-Roach, Chantelle / Lindstrom-Vautrin, Jonathan / Wang, Feiya / Rollins, Stuart / Bawa, Pushpinder Singh / Lu, Junjie / Tang, Yang / Beermann, Mary Lou / Schlaeger, Thorsten / Mahoney, John / Rowe, Steven M / Hawkins, Finn J / Kotton, Darrell N

American journal of respiratory and critical care medicine

2023 Volume 207, Issue 9, Page(s) 1249–1253

MeSH term(s)	Humans ; Induced Pluripotent Stem Cells ; Cystic Fibrosis ; Cells, Cultured ; Cell Line ; Cystic Fibrosis Transmembrane Conductance Regulator ; Cell Differentiation
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2023-02-21
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.202205-1010LE
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Article ; Online: Correction of Airway Stem Cells: Genome Editing Approaches for the Treatment of Cystic Fibrosis.

King, Nicholas E / Suzuki, Shingo / Barillà, Cristina / Hawkins, Finn J / Randell, Scott H / Reynolds, Susan D / Stripp, Barry R / Davis, Brian R

Human gene therapy

2020 Volume 31, Issue 17-18, Page(s) 956–972

Abstract: Cystic fibrosis (CF) is an autosomal recessive disease caused by variations in the cystic fibrosis transmembrane conductance regulator ( ...

Abstract	Cystic fibrosis (CF) is an autosomal recessive disease caused by variations in the cystic fibrosis transmembrane conductance regulator (
MeSH term(s)	Cystic Fibrosis/genetics ; Cystic Fibrosis/metabolism ; Cystic Fibrosis/therapy ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Gene Editing/methods ; Humans ; Respiratory Mucosa/cytology ; Respiratory Mucosa/metabolism ; Stem Cell Transplantation/methods ; Stem Cells/cytology ; Stem Cells/metabolism
Chemical Substances	CFTR protein, human ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2020-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2020.160
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Article ; Online: Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung.

eLife

2023 Volume 12

Abstract: Millions suffer from incurable lung diseases, and the donor lung shortage hampers organ transplants. Generating the whole organ in conjunction with the thymus is a significant milestone for organ transplantation because the thymus is the central organ to ...

Abstract	Millions suffer from incurable lung diseases, and the donor lung shortage hampers organ transplants. Generating the whole organ in conjunction with the thymus is a significant milestone for organ transplantation because the thymus is the central organ to educate immune cells. Using lineage-tracing mice and human pluripotent stem cell (PSC)-derived lung-directed differentiation, we revealed that gastrulating Foxa2 lineage contributed to both lung mesenchyme and epithelium formation. Interestingly, Foxa2 lineage-derived cells in the lung mesenchyme progressively increased and occupied more than half of the mesenchyme niche, including endothelial cells, during lung development.
MeSH term(s)	Mice ; Humans ; Animals ; Adult ; Endothelial Cells ; Pluripotent Stem Cells/metabolism ; Cell Differentiation ; Lung ; Blastocyst/metabolism ; Hepatocyte Nuclear Factor 3-beta/genetics ; Hepatocyte Nuclear Factor 3-beta/metabolism
Chemical Substances	Foxa2 protein, mouse ; Hepatocyte Nuclear Factor 3-beta (135845-92-0)
Language	English
Publishing date	2023-10-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.86105
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Article ; Online: A multimodal iPSC platform for cystic fibrosis drug testing.

Nature communications

2022 Volume 13, Issue 1, Page(s) 4270

Abstract: Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established ... ...

Abstract	Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants.
MeSH term(s)	Animals ; Cystic Fibrosis/drug therapy ; Cystic Fibrosis/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Epithelial Cells/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Ion Transport
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2022-07-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-31854-8
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