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Article ; Online: One person can make a difference

Amjad Horani / Steven L. Brody

ERJ Open Research, Vol 9, Iss

identification of people with a rare genetic lung disease

2023 Volume 2

Keywords	Medicine ; R
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	European Respiratory Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Impact of Motile Ciliopathies on Human Development and Clinical Consequences in the Newborn

Rachael M. Hyland / Steven L. Brody

Cells, Vol 11, Iss 125, p

2022 Volume 125

Abstract: Motile cilia are hairlike organelles that project outward from a tissue-restricted subset of cells to direct fluid flow. During human development motile cilia guide determination of the left-right axis in the embryo, and in the fetal and neonatal periods ...

Abstract	Motile cilia are hairlike organelles that project outward from a tissue-restricted subset of cells to direct fluid flow. During human development motile cilia guide determination of the left-right axis in the embryo, and in the fetal and neonatal periods they have essential roles in airway clearance in the respiratory tract and regulating cerebral spinal fluid flow in the brain. Dysregulation of motile cilia is best understood through the lens of the genetic disorder primary ciliary dyskinesia (PCD). PCD encompasses all genetic motile ciliopathies resulting from over 60 known genetic mutations and has a unique but often underrecognized neonatal presentation. Neonatal respiratory distress is now known to occur in the majority of patients with PCD, laterality defects are common, and very rarely brain ventricle enlargement occurs. The developmental function of motile cilia and the effect and pathophysiology of motile ciliopathies are incompletely understood in humans. In this review, we will examine the current understanding of the role of motile cilia in human development and clinical considerations when assessing the newborn for suspected motile ciliopathies.
Keywords	motile cilia ; human development ; primary ciliary dyskinesia ; neonate ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Engineering rotating apical-out airway organoid for assessing respiratory cilia motility

Piyumi Wijesekara / Prakarsh Yadav / Lydia A. Perkins / Donna B. Stolz / Jonathan M. Franks / Simon C. Watkins / Emily Reinoso Jacome / Steven L. Brody / Amjad Horani / Jian Xu / Amir Barati Farimani / Xi Ren

iScience, Vol 25, Iss 8, Pp 104730- (2022)

2022

Abstract: Summary: Motile cilia project from the airway apical surface and directly interface with inhaled external environment. Owing to cilia’s nanoscale dimension and high beating frequency, quantitative assessment of their motility remains a sophisticated task. ...

Abstract	Summary: Motile cilia project from the airway apical surface and directly interface with inhaled external environment. Owing to cilia’s nanoscale dimension and high beating frequency, quantitative assessment of their motility remains a sophisticated task. Here we described a robust approach for reproducible engineering of apical-out airway organoid (AOAO) from a defined number of cells. Propelled by exterior-facing cilia beating, the mature AOAO exhibited stable rotational motion when surrounded by Matrigel. We developed a computational framework leveraging computer vision algorithms to quantify AOAO rotation and correlated it with the direct measurement of cilia motility. We further established the feasibility of using AOAO rotation to recapitulate and measure defective cilia motility caused by chemotherapy-induced toxicity and by CCDC39 mutations in cells from patients with primary ciliary dyskinesia. We expect our rotating AOAO model and the associated computational pipeline to offer a generalizable framework to expedite the modeling of and therapeutic development for genetic and environmental ciliopathies.
Keywords	Molecular physiology ; Bioengineering ; Cell biology ; Science ; Q
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Regulation of cilia abundance in multiciliated cells

Rashmi Nanjundappa / Dong Kong / Kyuhwan Shim / Tim Stearns / Steven L Brody / Jadranka Loncarek / Moe R Mahjoub

eLife, Vol

2019 Volume 8

Abstract: Multiciliated cells (MCC) contain hundreds of motile cilia used to propel fluid over their surface. To template these cilia, each MCC produces between 100-600 centrioles by a process termed centriole amplification. Yet, how MCC regulate the precise ... ...

Abstract	Multiciliated cells (MCC) contain hundreds of motile cilia used to propel fluid over their surface. To template these cilia, each MCC produces between 100-600 centrioles by a process termed centriole amplification. Yet, how MCC regulate the precise number of centrioles and cilia remains unknown. Airway progenitor cells contain two parental centrioles (PC) and form structures called deuterosomes that nucleate centrioles during amplification. Using an ex vivo airway culture model, we show that ablation of PC does not perturb deuterosome formation and centriole amplification. In contrast, loss of PC caused an increase in deuterosome and centriole abundance, highlighting the presence of a compensatory mechanism. Quantification of centriole abundance in vitro and in vivo identified a linear relationship between surface area and centriole number. By manipulating cell size, we discovered that centriole number scales with surface area. Our results demonstrate that a cell-intrinsic surface area-dependent mechanism controls centriole and cilia abundance in multiciliated cells.
Keywords	centriole ; cilia ; basal body ; multiciliated ; deuterosome ; airway ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The effect of Dnaaf5 gene dosage on primary ciliary dyskinesia phenotypes

Amjad Horani / Deepesh Kumar Gupta / Jian Xu / Huihui Xu / Lis del Carmen Puga-Molina / Celia M. Santi / Sruthi Ramagiri / Steven K. Brennan / Jiehong Pan / Jeffrey R. Koenitzer / Tao Huang / Rachael M. Hyland / Sean P. Gunsten / Shin-Cheng Tzeng / Jennifer M. Strahle / Pleasantine Mill / Moe R. Mahjoub / Susan K. Dutcher / Steven L. Brody

JCI Insight, Vol 8, Iss

2023 Volume 11

Abstract: DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 ... ...

Abstract	DNAAF5 is a dynein motor assembly factor associated with the autosomal heterogenic recessive condition of motile cilia, primary ciliary dyskinesia (PCD). The effects of allele heterozygosity on motile cilia function are unknown. We used CRISPR-Cas9 genome editing in mice to recreate a human missense variant identified in patients with mild PCD and a second, frameshift-null deletion in Dnaaf5. Litters with Dnaaf5 heteroallelic variants showed distinct missense and null gene dosage effects. Homozygosity for the null Dnaaf5 alleles was embryonic lethal. Compound heterozygous animals with the missense and null alleles showed severe disease manifesting as hydrocephalus and early lethality. However, animals homozygous for the missense mutation had improved survival, with partially preserved cilia function and motor assembly observed by ultrastructure analysis. Notably, the same variant alleles exhibited divergent cilia function across different multiciliated tissues. Proteomic analysis of isolated airway cilia from mutant mice revealed reduction in some axonemal regulatory and structural proteins not previously reported in DNAAF5 variants. Transcriptional analysis of mouse and human mutant cells showed increased expression of genes coding for axonemal proteins. These findings suggest allele-specific and tissue-specific molecular requirements for cilia motor assembly that may affect disease phenotypes and clinical trajectory in motile ciliopathies.
Keywords	Genetics ; Pulmonology ; Medicine ; R
Subject code	572
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Efficient Generation and Transcriptomic Profiling of Human iPSC-Derived Pulmonary Neuroendocrine Cells

Pooja Hor / Vasu Punj / Ben A. Calvert / Alessandra Castaldi / Alyssa J. Miller / Gianni Carraro / Barry R. Stripp / Steven L. Brody / Jason R. Spence / Justin K. Ichida / Amy L. Ryan (Firth) / Zea Borok

iScience, Vol 23, Iss 5, Pp - (2020)

2020

Abstract: Summary: Expansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their ... ...

Abstract	Summary: Expansion of pulmonary neuroendocrine cells (PNECs) is a pathological feature of many human lung diseases. Human PNECs are inherently difficult to study due to their rarity (<1% of total lung cells) and a lack of established protocols for their isolation. We used induced pluripotent stem cells (iPSCs) to generate induced PNECs (iPNECs), which express core PNEC markers, including ROBO receptors, and secrete major neuropeptides, recapitulating known functions of primary PNECs. Furthermore, we demonstrate that differentiation efficiency is increased in the presence of an air-liquid interface and inhibition of Notch signaling. Single-cell RNA sequencing (scRNA-seq) revealed a PNEC-associated gene expression profile that is concordant between iPNECs and human fetal PNECs. In addition, pseudotime analysis of scRNA-seq results suggests a basal cell origin of human iPNECs. In conclusion, our model has the potential to provide an unlimited source of human iPNECs to explore PNEC pathophysiology associated with several lung diseases.
Keywords	Cell Biology ; Stem Cells Research ; Transcriptomics ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Functional partitioning of a liquid-like organelle during assembly of axonemal dyneins

Chanjae Lee / Rachael M Cox / Ophelia Papoulas / Amjad Horani / Kevin Drew / Caitlin C Devitt / Steven L Brody / Edward M Marcotte / John B Wallingford

eLife, Vol

2020 Volume 9

Abstract: Ciliary motility is driven by axonemal dyneins that are assembled in the cytoplasm before deployment to cilia. Motile ciliopathy can result from defects in the dyneins themselves or from defects in factors required for their cytoplasmic pre-assembly. ... ...

Abstract	Ciliary motility is driven by axonemal dyneins that are assembled in the cytoplasm before deployment to cilia. Motile ciliopathy can result from defects in the dyneins themselves or from defects in factors required for their cytoplasmic pre-assembly. Recent work demonstrates that axonemal dyneins, their specific assembly factors, and broadly-acting chaperones are concentrated in liquid-like organelles in the cytoplasm called DynAPs (Dynein Axonemal Particles). Here, we use in vivo imaging in Xenopus to show that inner dynein arm (IDA) and outer dynein arm (ODA) subunits are partitioned into non-overlapping sub-regions within DynAPs. Using affinity- purification mass-spectrometry of in vivo interaction partners, we also identify novel partners for inner and outer dynein arms. Among these, we identify C16orf71/Daap1 as a novel axonemal dynein regulator. Daap1 interacts with ODA subunits, localizes specifically to the cytoplasm, is enriched in DynAPs, and is required for the deployment of ODAs to axonemes. Our work reveals a new complexity in the structure and function of a cell-type specific liquid-like organelle that is directly relevant to human genetic disease.
Keywords	cilia ; axonemal dyneins ; DynAPs ; liquid-like organelle ; ciliopathy ; primary ciliary dykinesia ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Epithelial IL-33 appropriates exosome trafficking for secretion in chronic airway disease

Ella Katz-Kiriakos / Deborah F. Steinberg / Colin E. Kluender / Omar A. Osorio / Catie Newsom-Stewart / Arjun Baronia / Derek E. Byers / Michael J. Holtzman / Dawn Katafiasz / Kristina L. Bailey / Steven L. Brody / Mark J. Miller / Jennifer Alexander-Brett

JCI Insight, Vol 6, Iss

2021 Volume 4

Abstract: IL-33 is a key mediator of chronic airway disease driven by type 2 immune pathways, yet the nonclassical secretory mechanism for this cytokine remains undefined. We performed a comprehensive analysis in human airway epithelial cells, which revealed that ... ...

Abstract	IL-33 is a key mediator of chronic airway disease driven by type 2 immune pathways, yet the nonclassical secretory mechanism for this cytokine remains undefined. We performed a comprehensive analysis in human airway epithelial cells, which revealed that tonic IL-33 secretion is dependent on the ceramide biosynthetic enzyme neutral sphingomyelinase 2 (nSMase2). IL-33 is cosecreted with exosomes by the nSMase2-regulated multivesicular endosome (MVE) pathway as surface-bound cargo. In support of these findings, human chronic obstructive pulmonary disease (COPD) specimens exhibited increased epithelial expression of the abundantly secreted IL33Δ34 isoform and augmented nSMase2 expression compared with non-COPD specimens. Using an Alternaria-induced airway disease model, we found that the nSMase2 inhibitor GW4869 abrogated both IL-33 and exosome secretion as well as downstream inflammatory pathways. This work elucidates a potentially novel aspect of IL-33 biology that may be targeted for therapeutic benefit in chronic airway diseases driven by type 2 inflammation.
Keywords	Immunology ; Pulmonology ; Medicine ; R
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A liquid-like organelle at the root of motile ciliopathy

Ryan L Huizar / Chanjae Lee / Alexander A Boulgakov / Amjad Horani / Fan Tu / Edward M Marcotte / Steven L Brody / John B Wallingford

eLife, Vol

2018 Volume 7

Abstract: Motile ciliopathies are characterized by specific defects in cilia beating that result in chronic airway disease, subfertility, ectopic pregnancy, and hydrocephalus. While many patients harbor mutations in the dynein motors that drive cilia beating, the ... ...

Abstract	Motile ciliopathies are characterized by specific defects in cilia beating that result in chronic airway disease, subfertility, ectopic pregnancy, and hydrocephalus. While many patients harbor mutations in the dynein motors that drive cilia beating, the disease also results from mutations in so-called dynein axonemal assembly factors (DNAAFs) that act in the cytoplasm. The mechanisms of DNAAF action remain poorly defined. Here, we show that DNAAFs concentrate together with axonemal dyneins and chaperones into organelles that form specifically in multiciliated cells, which we term DynAPs, for dynein axonemal particles. These organelles display hallmarks of biomolecular condensates, and remarkably, DynAPs are enriched for the stress granule protein G3bp1, but not for other stress granule proteins or P-body proteins. Finally, we show that both the formation and the liquid-like behaviors of DynAPs are disrupted in a model of motile ciliopathy. These findings provide a unifying cell biological framework for a poorly understood class of human disease genes and add motile ciliopathy to the growing roster of human diseases associated with disrupted biological phase separation.
Keywords	DynAP ; heat shock protein ; cilia ; dynein ; primary ciliary dyskinesia ; chaperone ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Autophagy regulates DUOX1 localization and superoxide production in airway epithelial cells during chronic IL-13 stimulation

John D. Dickinson / Jenea M. Sweeter / Kristi J. Warren / Iman M. Ahmad / Xavier De Deken / Matthew C. Zimmerman / Steven L. Brody

Redox Biology, Vol 14, Iss , Pp 272-

2018 Volume 284

Abstract: The airway epithelium is a broad interface with the environment, mandating well-orchestrated responses to properly modulate inflammation. Classically, autophagy is a homeostatic pathway triggered in response to external cellular stresses, and is elevated ...

Abstract	The airway epithelium is a broad interface with the environment, mandating well-orchestrated responses to properly modulate inflammation. Classically, autophagy is a homeostatic pathway triggered in response to external cellular stresses, and is elevated in chronic airway diseases. Recent findings highlight the additional role of autophagy in vesicle trafficking and protein secretion, implicating autophagy pathways in complex cellular responses in disease. Th2 cytokines, IL-13 and IL-4, are increased in asthma and other airway diseases contributing to chronic inflammation. Previously, we observed that IL-13 increases reactive oxygen species (ROS) in airway epithelial cells in an autophagy-dependent fashion. Here, we tested our hypothesis that autophagy is required for IL-13-mediated superoxide production via the NADPH oxidase DUOX1. Using a mouse model of Th2-mediated inflammation induced by OVA-allergen, we observed elevated lung amounts of IL-13 and IL-4 accompanied by increased autophagosome levels, determined by LC3BII protein levels and immunostaining. ROS levels were elevated and DUOX1 expression was increased 70-fold in OVA-challenged lungs. To address the role of autophagy and ROS in the airway epithelium, we treated primary human tracheobronchial epithelial cells with IL-13 or IL-4. Prolonged, 7-day treatment increased autophagosome formation and degradation, while brief activation had no effect. Under parallel culture conditions, IL-13 and IL-4 increased intracellular superoxide levels as determined by electron paramagnetic resonance (EPR) spectroscopy. Prolonged IL-13 activation increased DUOX1, localized at the apical membrane. Silencing DUOX1 by siRNA attenuated IL-13-mediated increases in superoxide, but did not reduce autophagy activities. Notably, depletion of autophagy regulatory protein ATG5 significantly reduced superoxide without diminishing total DUOX1 levels. Depletion of ATG5, however, diminished DUOX1 localization at the apical membrane. The findings suggest non-canonical autophagy ...
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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