scholarly journals An Autoantigen Atlas from Human Lung HFL1 Cells Offers Clues to Neurological and Diverse Autoimmune Manifestations of COVID-19

2021 ◽  
Author(s):  
Julia Y. Wang ◽  
Wei Zhang ◽  
Michael W. Roehrl ◽  
Victor B. Roehrl ◽  
Michael H. Roehrl
Keyword(s):  
Human Lung ◽  
Dermatan Sulfate ◽  
Neuronal Cell ◽  
Fetal Lung ◽  
Neuronal Cell Body ◽  
Autoantibody Production ◽  
Vast Number ◽  
Mrna Metabolism ◽  
Altered Proteins ◽  
Human Fetal Lung

AbstractCOVID-19 is accompanied by a myriad of both transient and long-lasting autoimmune responses. Dermatan sulfate (DS), a glycosaminoglycan crucial for wound healing, has unique affinity for autoantigens (autoAgs) from apoptotic cells. DS-autoAg complexes are capable of stimulating autoreactive B cells and autoantibody production. Using DS affinity, we identified an autoantigenome of 408 proteins from human fetal lung fibroblast HFL11 cells, at least 231 of which are known autoAgs. Comparing with available COVID data, 352 proteins of the autoantigenome have thus far been found to be altered at protein or RNA levels in SARS-Cov-2 infection, 210 of which are known autoAgs. The COVID-altered proteins are significantly associated with RNA metabolism, translation, vesicles and vesicle transport, cell death, supramolecular fibrils, cytoskeleton, extracellular matrix, and interleukin signaling. They offer clues to neurological problems, fibrosis, smooth muscle dysfunction, and thrombosis. In particular, 150 altered proteins are related to the nervous system, including axon, myelin sheath, neuron projection, neuronal cell body, and olfactory bulb. An association with the melanosome is also identified. The findings from our study illustrate a strong connection between viral infection and autoimmunity. The vast number of COVID-altered proteins with propensity to become autoAgs offers an explanation for the diverse autoimmune complications in COVID patients. The variety of autoAgs related to mRNA metabolism, translation, and vesicles raises concerns about potential adverse effects of mRNA vaccines. The COVID autoantigen atlas we are establishing provides a detailed molecular map for further investigation of autoimmune sequelae of the pandemic.Summary sentenceAn autoantigenome by dermatan sulfate affinity from human lung HFL1 cells may explain neurological and autoimmune manifestations of COVID-19

scholarly journals MORPHOGENETIC ASPECTS OF MULTILAYERING IN PETRI DISH CULTURES OF HUMAN FETAL LUNG FIBROBLASTS

1969 ◽  
Vol 41 (1) ◽  
pp. 298-311 ◽  
Author(s):  
Tom Elsdale ◽  
Robert Foley
Keyword(s):  
Extracellular Matrix ◽  
Human Lung ◽  
Petri Dish ◽  
Fetal Lung ◽  
Single Species ◽  
Lung Fibroblasts ◽  
Human Lung Fibroblasts ◽  
Spontaneous Aggregation ◽  
Control Hypothesis ◽  
Human Fetal Lung

Randomly seeded Petri dish cultures of embryonic human lung fibroblasts generate, in the course of their growth, highly ordered cellular arrangements. Thick, bilaterally symmetrical ridges with an axial polarity and an orthogonal, multilayered internal organization are observed within stationary cultures. The generation of these structures has been investigated. Ridges result from the spontaneous aggregation of cells in postconfluent cultures brought about by directed cell movements. These movements are promoted by the localized production of extracellular matrix sheets containing collagen, which provide new substrates for cellular colonization. Cells that have colonized one matrix substrate may secrete another above themselves, which will in turn be colonized. By a continuation of this cycle, thick stacks consisting of alternate layers of cells and matrix are produced to yield the observed aggregations. The distribution and shape of ridges in a culture imply that matrix substrates are confined to specific locations. The suggested control hypothesis assumes that all the cells in fibroblast cultures are potential producers of a single species of matrix. The serviceability of this matrix as a substrate for cellular colonization, however, is destroyed if the producer cells are motile. Matrix substrates, therefore, are only made by nonmotile cells.

scholarly journals Effect of Intrauterine Smoke Exposure on microRNA-15a Expression in Human Lung Development and Subsequent Asthma Risk

Healthcare ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 536
Author(s):  
Sunita Sharma ◽  
Alvin T. Kho ◽  
Divya Chhabra ◽  
Kathleen Haley ◽  
Carrie Vyhlidal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Development ◽  
Human Lung ◽  
Expression Profiles ◽  
Fetal Lung ◽  
In Utero ◽  
Differentially Expressed ◽  
Mouse Lung ◽  
Asthma Susceptibility ◽  
Human Fetal Lung

Background: In utero smoke (IUS) exposure is associated with asthma susceptibility. Objective: We sought to test the hypothesis that changes in miRNA expression by IUS exposure during human lung development is associated with asthma susceptibility. Methods: Gene expression was profiled from 53 IUS unexposed and 51 IUS exposed human fetal lung tissues. We tested for the differential expression of miRNAs across post-conception age and by IUS using linear models with covariate adjustment. We tested the IUS-associated miRNAs for association with their gene expression targets using pair-wise inverse correlation. Using our mouse model, we investigated the persistence of the IUS-associated miRNA signature using RT-PCR from the lungs of mouse pups with and without IUS at postnatal day 14. MiRNAs were then tested for association with asthma and exacerbations using whole blood gene expression profiles from Asthma BRIDGE. Results: Five miRNAs were differentially expressed across post-conception age (adjusted p < 0.0002) including two that were differentially expressed by IUS exposure in human fetal lung (p < 0.05). MiR-15a was differentially expressed by post-conception age (p = 0.00002), IUS exposure in human fetal lung (p = 0.005), and in the post-natal mouse lung (p = 0.01). MiR-15a was also associated with the in utero expression of GSDMB (adjusted p = 0.0002), a known childhood asthma gene and with asthma exacerbations (p = 0.0009) in Asthma BRIDGE. Thus, miR-15a is expressed during human lung development, is impacted by IUS exposure, regulates the intrauterine expression of asthma genes, and is associated with asthma severity. Conclusions: These results provide evidence for the role of miR-15a in the fetal origin of asthma.

scholarly journals Characterization of CD34+cells isolated from human fetal lung

2003 ◽  
Vol 284 (2) ◽  
pp. L395-L401 ◽  
Author(s):  
Michael J. Acarregui ◽  
Katherine M. England ◽  
Joshua T. Richman ◽  
Jennifer L. Littig
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Lung Tissue ◽  
Human Lung ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Fetal Lung ◽  
Pcr Analysis ◽  
Isolated Cells ◽  
Human Fetal Lung

The large capillary mass of the newborn lung demands the presence of endothelial cell precursors in lung tissue before development of the pulmonary capillary bed. The objective of this investigation was to isolate and characterize putative endothelial cell precursors from developing human lung. CD34, a cell surface marker for hematopoietic progenitor cells, endothelial precursor cells, and small vessel endothelial cells, was employed as an immunological “handle” for the selection of the desired cells. When CD34+cells were isolated from midtrimester human fetal lung tissue, then maintained in culture, the isolated cells expressed immunoreactivity for the endothelial cell marker von Willebrand factor and the vascular endothelial growth factor receptors KDR and Flt-1. However, only 5% or fewer of the cells expressed PECAM, an important factor in cell-cell interactions and a marker for endothelial cells associated with vessels. The CD34+cells endocytosed acetylated low-density lipoprotein and formed capillary-like structures when incubated in a cushion of Matrigel. RT-PCR analysis of mRNA for endothelial cell-related proteins Flt-1, Tie-2, and endothelial nitric oxide synthase demonstrated expression of these mRNAs by the isolated cells for at least 16 cell passages. These observations demonstrate that capillary endothelial cell precursors can be isolated from developing human lung and maintained in cell culture. These cells represent a potentially important tool for investigating the regulation of mechanisms governing development of the air-blood barrier in the human lung.

scholarly journals A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates

2022 ◽  
Author(s):  
Peng He ◽  
Kyungtae Lim ◽  
Dawei Sun ◽  
Jan Patrick Pett ◽  
Quitz Jeng ◽  
...  
Keyword(s):  
Single Cell ◽  
Lung Development ◽  
Cell Imaging ◽  
Human Lung ◽  
Cell Signalling ◽  
Fetal Lung ◽  
Web Interface ◽  
General Utility ◽  
Single Cell Imaging ◽  
Human Fetal Lung

We present a multiomic cell atlas of human lung development that combines single cell RNA and ATAC sequencing, high throughput spatial transcriptomics and single cell imaging. Coupling single cell methods with spatial analysis has allowed a comprehensive cellular survey of the epithelial, mesenchymal, endothelial and erythrocyte/leukocyte compartments from 5-22 post conception weeks. We identify new cell states in all compartments. These include developmental-specific secretory progenitors that resemble cells in adult fibrotic lungs and a new subtype of neuroendocrine cell related to human small cell lung cancer; observations which strengthen the connections between development and disease/regeneration. Our datasets are available for the community to download and interact with through our web interface (https://fetal-lung.cellgeni.sanger.ac.uk). Finally, to illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signalling and transcription factor hierarchies which we test using organoid models.

Collagen secretion mediated by NMDR activation in human fetal lung fibroblasts

2010 ◽  
Vol 34 (8) ◽  
pp. S70-S70
Author(s):  
MingJie WANG ◽  
ZiQiang LUO ◽  
Mei LU ◽  
LiHong SHANG ◽  
ShaoJie YUE
Keyword(s):  
Fetal Lung ◽  
Lung Fibroblasts ◽  
Collagen Secretion ◽  
Human Fetal Lung

Glucocorticoid regulation of epithelial sodium channel genes in human fetal lung

1997 ◽  
Vol 273 (1) ◽  
pp. L227-L233 ◽  
Author(s):  
V. C. Venkatesh ◽  
H. D. Katzberg
Keyword(s):  
Rna Polymerase Ii ◽  
Actinomycin D ◽  
Critical Role ◽  
Fetal Lung ◽  
Explant Culture ◽  
Late Gestation ◽  
Na Channel ◽  
Second Trimester ◽  
Cyclic Monophosphate ◽  
Human Fetal Lung

Pulmonary epithelial Na+ channels (ENaC), composed of three distinct subunits (alpha, beta, and gamma), play a critical role in the regulation of fluid reabsorption from airspaces of late-gestation fetal lung. We studied the expression of ENaC subunit genes in cultured human fetal lung. All three mRNAs were expressed at low levels in second trimester lung (13-32% of adult values at 24 wk gestation). There was a spontaneous increase of approximately threefold over preculture values of all three subunits within 24 h of explant culture in serum-free Waymouth's medium. Dexamethasone (Dex) induced all three mRNAs by two- to threefold. Maximal induction was noted by 8 h with 30-100 nM Dex and half-maximal stimulation with 3-10 nM Dex. Cycloheximide decreased basal expression of all three subunits by 8 h but did not alter the response to Dex. Actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB), inhibitors of RNA polymerase II, decreased the basal and the Dex-induced expression of all three subunits with a more marked effect on human hENaC-gamma than on hENaC-alpha or hENaC-beta. Under conditions where transcription was blocked by actinomycin D or DRB, Dex did not alter the stability of the three mRNAs. Triiodothyronine (T3) at low (2 nM) or high (100 nM) concentrations had no effect on the expression of the three subunits in the presence or absence of low (10 nM) or high (100 nM) concentrations of Dex for 8 or 24 h. Similarly, 8-bromoadenosine 3',5'-cyclic monophosphate (2 microM) had no effect on basal or Dex-induced increase in the three subunits. We conclude that the three Na+ channel subunit genes are expressed in second trimester human fetal lung and are coordinately upregulated by glucocorticoid hormones but not by T3 or adenosine 3',5'-cyclic monophosphate. Glucocorticoid induction is receptor mediated, is primarily transcriptional, and does not require the induction of an intermediate protein for transcriptional enhancement. We speculate that induction of lung ENaC may contribute to the beneficial effects of antenatal glucocorticoids in premature babies.

Fabrication and Cytotoxicity Studies of the TiO2 Doped with Copper-Based Nanocomposite Particles

2011 ◽  
Vol 695 ◽  
pp. 393-396 ◽  
Author(s):  
Chang Mao Hung
Keyword(s):  
Fetal Lung ◽  
Copper Nitrate ◽  
Tissue Cell ◽  
Nanocomposite Particles ◽  
Toxicological Effect ◽  
Cytotoxicity Studies ◽  
Cultured Human Cells ◽  
Cytotoxicity Assessment ◽  
Human Fetal Lung ◽  
Dispersion Character

Since the growing interest in the manufacture and environmental applications of nanocomposites consisting of CuO and TiO2nanoparticles (NPs), related toxicological effect and interaction with cellular structures for these newly developed materials are still unknown. Recent literature reveals that nanosized CuO and TiO2particles have cytotoxicity risks and ability to cause oxidative stress on health. This work considers the CuO doped TiO2nanocomposite particles were synthesized via a coprecipitation method with aqueous solutions as precursors of copper nitrateand titanium dioxide. Moreover, the nanocomposite particles were characterized using TGA-DTA, UV-Vis and TEM measurements. The calcination temperature was selected at 873 K. The nanocomposite particles were characterized by TEM, as the primary particles, aggregates ranged from 30 to 100 nm and have a good dispersion character. Cell cytotoxicity assessment and the percentage cell survival was determined by using 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenol)-2-(4-sulfophenyl)-2H-tetrazoli um (MTS) assay on human fetal lung tissue cell (MRC-5). The experimental results show that the CuO doped TiO2nanocomposite particles cause potential cytotoxicity effect in cultured human cells.

Comparison of WI-38, MRC-5, and IMR-90 cell strains for isolation of viruses from clinical specimens

1978 ◽  
Vol 7 (4) ◽  
pp. 368-371
Author(s):  
H M Friedman ◽  
C Koropchak
Keyword(s):  
Tissue Culture ◽  
Life Span ◽  
Fetal Lung ◽  
Cell Strain ◽  
Viral Isolation ◽  
Clinical Specimens ◽  
Cell Strains ◽  
Viral Diagnosis ◽  
Human Fetal Lung ◽  
Speed Of Onset

With the diminishing supply of the human fetal lung WI-38 cell strain, a replacement for viral isolation is needed. Two candidates are the human fetal lung strains MRC-5 and IMR-90. A comparison of WI-38, MRC-5, and IMR-90 was performed to evaluate efficiency and speed of viral isolation, clarity of cytophatic effect, and ease of growing the cells. The inocula were clinical specimens rather than tissue culture-adapted isolates. Frozen samples of 46 specimens that had previously yielded an isolate on WI-38 were thawed and inoculated onto WI-38, MRC-5, and IMR-90 cells. In addition, 95 freshly taken clinical specimens uf undetermined infectivity were inoculated onto the cell strains. Viral recovery rates were similar on all three strains, as were the appearance and speed of onset of the cytophatic effect. MRC-5 and WI-38 cells remained healthy until generation 36, whereas IMR-90 cells went into crisis by generation 20. The longer life span of the MRC-5 cells makes them more suitable than IMR-90 cells to replace the WI-38 strain for routine use in viral diagnosis.

Neurotransmission in neonatal rat cardiac ganglion in situ

1990 ◽  
Vol 259 (4) ◽  
pp. H997-H1005 ◽  
Author(s):  
G. R. Seabrook ◽  
L. A. Fieber ◽  
D. J. Adams
Keyword(s):  
Neuronal Cell ◽  
Nerve Fibers ◽  
Heart Beat ◽  
Neonatal Rat ◽  
Neuronal Cell Body ◽  
High Frequency Stimulation ◽  
Excitatory Postsynaptic Potential ◽  
Cardiac Ganglion ◽  
Cardiac Ganglia

The intrinsic cardiac ganglia of the neonatal rat heart in situ were studied using electrophysiological and histochemical techniques. The vagal branches innervating the atrial myocardium and cardiac ganglia were identified and individual ganglion cells visualized using Hoffman modulation contrast optics. Histochemical studies revealed the presence of acetylcholinesterase activity associated with neuronal cell bodies and fibers, catecholamine-containing, small intensely fluorescent cells, and cell bodies and nerve fibers immunoreactive for vasoactive intestinal polypeptide. Intracellular recordings from the "principal" cells of the rat cardiac ganglion in situ revealed a fast excitatory postsynaptic potential (EPSP) evoked after electrical stimulation of the vagus nerve, which was inhibited by the nicotinic receptor antagonist, mecamylamine. No spontaneously firing neurons were found, although infrequent (less than 2 min-1) spontaneous miniature EPSPs were observed in most neurons. The quantal content of neurally evoked responses was between 10 and 30 quanta, and the presence of multiple EPSPs in some cells suggested polyneuronal innervation. The neurally evoked EPSP amplitude was dependent on the rate of nerve stimulation, decreasing with increasing frequency of stimulation. Neurons exhibited a sustained depolarization during high frequency stimulation (greater than 1 Hz), and in approximately 15% of the cells a slow depolarization lasting 1-3 min was observed after a train of stimuli. The presence of catecholamine- and neuropeptide-containing neuronal cell body fibers in neonatal rat cardiac ganglia in situ, along with neurally evoked postsynaptic responses resistant to cholinergic ganglionic blockers, suggests a role for noncholinergic transmission in the regulation of the mammalian heart beat.

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