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PubMed2026

Human and mouse adrenal glands are characterized by species-specific steroidogenic states and tissue turnover.

The adult adrenal cortex undergoes constant renewal, yet underlying human-specific mechanisms remain poorly understood. Here we generated single-cell and spatial transcriptomic atlases of adult human and mouse adrenal glands, leveraging single-cell-resolution spatial data and a rare clonal mosaic case for lineage inference. In humans, we identified age-associated zona glomerulosa (ZG) cell states with direct cortisol synthesis capacity and sex-specific differences in inferred cholesterol balance. Cross-species comparison revealed conserved aldosterone-producing ZG but notable divergence in zona fasciculata markers, absence of zona reticularis homologs in mice and differential SHH-WNT4 signaling in proliferating cells. We uncovered human WT1- capsule-to-ZG transition and vascular smooth muscle cell-to-steroidogenic transitions supported by mosaic lineage evidence. We revealed dispersed proliferating cortical SF1+EZH2+ cells throughout the human cortex in contrast with ZG restriction in mice. Taken together, our data expand the centripetal renewal model and establish a comparative framework for human adrenocortical biology.

Animals↗

PubMed2005

Transcriptomic analyses support the similarity of gene expression between brain and testis in human as well as mouse.

We previously revealed similarity in gene expression patterns between human brain and testis, based on digital differential display analyses of 760 human Unigenes. In the present work, we reanalyzed the gene expression data in many tissues of human and mouse for a large number of genes almost covering the respective whole genomes. The results indicated that both in human and in mouse, the gene expression profiles exhibited by brain, cerebellum and testis are most similar to each other compared with other tissues.

Animals↗

PubMed2026

Dysregulated Sheddase Signalling as a Molecular Driver of Plaque Instability Revealed by Integrative Transcriptomics.

Atherosclerosis is a major cause of mortality due to chronic and progressive low-grade inflammation and fibroproliferative remodelling of the intima of arteries. Comprehensive understanding of the interplay between plaque biology and the mechanisms underlying plaque vulnerability and rupture is essential. Here, we aimed to investigate the transcriptomic profiles of stable and unstable atherosclerotic plaques using RNA sequencing data from human carotid atherosclerotic plaque samples based on next-generation knowledge discovery (NGKD) methods. High-throughput RNA-seq data from plaques dissected in stable and unstable regions of four patients were obtained from the Gene Expression Omnibus (GEO) database. GEO RNA-seq Experiments Interactive Navigator (GREIN) software was used to obtain raw gene-level counts and filtered metadata for this dataset. The data were further filtered and normalized using Express analyst to derive differentially expressed genes (DEGs) in unstable plaques compared to stable plaques. The DEGs were further analysed using WebGestalt, STRING DB, preranked gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) software. We identified 4792 DEGs in unstable plaques based on a p-value cutoff of < 0.05. NGKD analysis revealed that the sheddase pathway, collagen degradation, activation of matrix metalloproteinases (MMPs), and extracellular matrix (ECM) degradation ranked among the top five upregulated pathways, whereas the inhibition of MMPs and smooth muscle contraction pathways were identified as the most prominent downregulated pathways in unstable plaques. We found that the sheddase pathway was one of the most significantly upregulated canonical pathways in unstable plaques and this finding opens new avenues for potential therapeutic interventions in patients with atherosclerosis.

Humans↗

PubMed2026

Exploration and experimental verification of triaptosis-related prognostic genes and cells in gastric cancer.

BACKGROUND: Triaptosis is a recently characterized form of programmed cell death with unclear implications in cancer. This study aimed to investigate the prognostic significance and biological relevance of triaptosis in gastric cancer (GC). METHODS: Transcriptomic and clinical data from TCGA-STAD and GSE62254, and single-cell RNA sequencing data from GSE183904 were analyzed. Triaptosis-related gene (TRG) scores were calculated using single-sample gene set enrichment analysis. Differentially expressed genes identified in TRG-score and GC-versus-normal comparisons underwent functional enrichment, Cox regression, and least absolute shrinkage and selection operator regression to develop an externally validated signature. Immune profiles, pathway activity, somatic mutations, tumor mutational burden (TMB), predicted drug sensitivity, and clinical features were compared by risk group. Single-cell analyses assessed TRG activity, prognostic gene expression, cell-cell communication, and pseudotime. Reverse transcription-quantitative PCR and Western blotting assessed mRNA expression and protein levels, respectively. RESULTS: A TRG-based prognostic model comprising ASPN, GRB14, and VTN was developed and externally validated, effectively distinguishing patients into two distinct risk groups with notably different survival outcomes. mRNA expression of all three genes and their protein levels were significantly higher in SGC-7901 cells than in GES-1 cells. High-risk patients had higher stromal scores and distinct immune profiles; 15 immune cell types differed between groups. Single-cell analysis revealed fibroblasts and pericytes among high-TRG-active cell types. Prognostic genes were significantly overexpressed in fibroblasts, which also showed high TRG activity. Fibroblasts demonstrated enhanced communication with pericytes, whereas tumor-derived fibroblasts showed weaker communication with macrophages, indicating immune microenvironment remodeling. CONCLUSION: The three-gene prognostic signature predicted GC prognosis and was associated with distinct immune and genomic features, suggesting potential value for risk stratification and personalized treatment.

Humans↗

PubMed2025

Reversible phenotypic resistance to phage infection via capsule downregulation in Klebsiella pneumoniae.

Capsule loss is a major mechanism by which bacteria evade phage infection. This has traditionally been attributed to mutations in capsule biosynthesis genes. Here, we investigated phage resistance in Klebsiella pneumoniae, a medically relevant encapsulated bacterium. Phage infection rapidly selected for resistant acapsular cells. As expected, transcriptomic analysis revealed a marked downregulation of capsule biosynthesis genes. However, full genome sequencing showed that capsule loss occurred without evidence of mutations, and acapsular phage-resistant cells were able to rapidly restore their capsule once phage pressure was removed. These findings highlight that phage-driven selective pressure can act on non-heritable variation in gene expression, providing a faster and more flexible resistance mechanism compared to the traditional mutation-selection process. This reversible resistance may complicate predictability and limit the long-term efficacy of phage therapy.

Cell biology↗

PubMed2005

Systemic signalling of environmental cues in Arabidopsis leaves.

Light intensity and atmospheric CO2 partial pressure are two environmental signals known to regulate stomatal numbers. It has previously been shown that if a mature Arabidopsis leaf is supplied with either elevated CO2 (750 ppm instead of ambient at 370 ppm) or reduced light levels (50 micromol m-2 s-1 instead of 250 micromol m-2 s-1), the young, developing leaves that are not receiving the treatment grow with a stomatal density as if they were exposed to the treatment. But the signal(s) that it is believed is generated in the mature leaves and transmitted to developing leaves are largely unknown. Photosynthetic rates of treated, mature Arabidopsis leaves increased in elevated CO2 and decreased when shaded, as would be expected. Similarly, the levels of sugars (glucose, fructose, and sucrose) in the treated mature leaves increased in elevated CO2 and decreased with shade treatment. The levels of sugar in developing leaves were also measured and it was found that they mirrored this result even though they were not receiving the shade or elevated CO2 treatment. To investigate the effect of these treatments on global gene expression patterns, transcriptomics analysis was carried out using Affymetrix, 22K, and ATH1 arrays. Total RNA was extracted from the developing leaves after the mature leaves had received either the ambient control treatment, the elevated CO2 treatment, or the shade treatment, or both elevated CO2 and shade treatments for 2, 4, 12, 24, 48, or 96 h. The experiment was replicated four times. Two other experiments were also conducted, one to compare and contrast gene expression in response to plants grown at elevated CO2 and the other to look at the effect of these treatments on the mature leaf. The data were analysed and 915 genes from the untreated, signalled leaves were identified as having expression levels affected by the shade treatment. These genes were then compared with those whose transcript abundance was affected by the shade treatment in the mature treated leaves (1181 genes) and with 220 putative 'stomatal signalling' genes previously identified from studies of the yoda mutant. The results of these experiments and how they relate to environmental signalling are discussed, as well as possible mechanisms for systemic signalling.

Acclimatization↗

PubMed2004

Characterization of antirrhinum petal development and identification of target genes of the class B MADS box gene DEFICIENS.

The class B MADS box transcription factors DEFICIENS (DEF) and GLOBOSA (GLO) of Antirrhinum majus together control the organogenesis of petals and stamens. Toward an understanding of how the downstream molecular mechanisms controlled by DEF contribute to petal organogenesis, we conducted expression profiling experiments using macroarrays comprising >11,600 annotated Antirrhinum unigenes. First, four late petal developmental stages were compared with sepals. More than 500 ESTs were identified that comprise a large number of stage-specifically regulated genes and reveal a highly dynamic transcriptional regulation. For identification of DEF target genes that might be directly controlled by DEF, we took advantage of the temperature-sensitive def-101 mutant. To enhance the sensitivity of the profiling experiments, one petal developmental stage was selected, characterized by increased transcriptome changes that reflect the onset of cell elongation processes replacing cell division processes. Upon reduction of the DEF function, 49 upregulated and 52 downregulated petal target genes were recovered. Eight target genes were further characterized in detail by RT-PCR and in situ studies. Expression of genes responding rapidly toward an altered DEF activity is confined to different petal tissues, demonstrating the complexity of the DEF function regulating diverse basic processes throughout petal morphogenesis.

Antirrhinum↗

PubMed2024

Effects of different temperatures on chondrocyte growth: a transcriptomic analysis.

BACKGROUND: Our previous study demonstrated that temperature-related microwave ablation (MWA) can safely modulate growth plates of piglets' vertebrae. Therefore, this study is designed to investigate the effects of different temperatures on chondrocyte viability and the underlying molecular mechanisms in vitro. METHODS: Following a 10-minute treatment at different temperatures (37 °C, 40 °C, 42 °C, 44 °C, 46 °C, 48 °C, and 50 °C), CCK-8 assay was used to examine the viability of ATDC5 cells at 12 h. Differentially expressed genes (DEGs) and the hub genes in ATDC5 cells treated at 37 °C, 40 °C and 44 °C were identified using RNA-seq. The expression of hub genes in ATDC5 cells was validated using RT-qPCR. RESULTS: Compared with 37 °C, exposure to 40 °C significantly increased the viability of ATDC5 cells, while 42 °C had no significant effect. Additionally, exposure to 44 °C, 46 °C, 48 °C, and 50 °C exhibited the opposite pattern, with ATDC5 cells being particularly less than 50% active after treatment at 46 °C, 48 °C, and 50 °C. Differential expression analysis identified 179, 374 and 221 DEGs in the comparisons of 40 °C vs. 37 °C, 44 °C vs. 37 °C, and 44 °C vs. 40 °C, respectively. These DEGs predominantly regulated proliferation, differentiation, necrosis, inflammatory and immune responses, and ECM synthesis/degradation. Furthermore, they were associated with the Ras, PI3K/AKT, mTOR, cAMP, and MAPK pathways. Agt, Hspa1a, Hspb1, and Nlrc4 were identified as hub genes in DEGs, and RT-qPCR confirmed that the mRNA expression patterns of these hub genes in ATDC5 cells were largely consistent with the RNA-seq results. CONCLUSION: The regulation of chondrocyte viability by temperature is associated with Ras, PI3K/AKT, mTOR, cAMP, and MAPK pathways. Additionally, Agt, Hspa1a, Hspb1, and Nlrc4 may be the key regulatory genes in this process.

Chondrocytes↗

PubMed2005

Proteome mapping of mature pollen of Arabidopsis thaliana.

The male gametophyte of Arabidopsis is a three-celled pollen grain that is thought to contain almost all the mRNAs needed for germination and rapid pollen tube growth. We generated a reference map of the Arabidopsis mature pollen proteome by using multiple protein extraction techniques followed by 2-DE and ESI-MS/MS. We identified 135 distinct proteins from a total of 179 protein spots. We found that half of the identified proteins are involved in metabolism (20%), energy generation (17%), or cell structure (12%); these percentages are similar to those determined for the pollen transcriptome and this similarity is consistent with the idea that in addition to the mRNAs, the mature pollen grain contains proteins necessary for germination and rapid pollen tube growth. We identified ten proteins of unknown function, three of which are flower- or pollen-specific, and we identified nine proteins whose RNAs were absent from the transcriptome, seven of which are involved in metabolism, energy generation, or cell wall structure. Our work complements and extends recent analyses of the pollen transcriptome.

Amino Acid Sequence↗

PubMed2025

Amylin inhibits gastric cancer progression by targeting CCN1 and affecting the PI3K/AKT signalling pathway.

METHODS: This study used a combination of in vitro and in vivo experiments to investigate the role of amylin in the progression of GC. The expression of amylin in GC and its clinical correlation were evaluated using 38 pairs of GC and healthy human clinical samples. In vitro studies, human GC cell lines were treated with amylin to evaluate the effects of amylin on the proliferation, apoptosis and migration of GC cells. In in vivo studies, xenograft mouse models were established by subcutaneous injection of GC cells into nude mice, followed by treatment with amylin to assess tumor growth. Finally, Next-Generation Sequencing Technology (RNA-seq) was used to explore the potential mechanism of amylin on GC. RESULTS: We found that amylin expression was reduced in GC compared to adjacent normal gastric tissues and that elevated amylin expression was negatively correlated with adverse pathological factors (p < 0.05). Additionally, we demonstrated that amylin impeded the growth, invasion, migration, and colony formation of GC cells and suppressed the epithelial-to-mesenchymal transformation of these cells (p < 0.05). Tumour xenograft model experiments confirmed the tumour-suppressive effect of amylin in subcutaneous tumours in nude mice (p < 0.05). Transcriptome sequencing (RNA-seq) revealed that amylin significantly down-regulated CCN1 gene expression in GC cells (p < 0.001). Further intervention targeting CCN1 verified its significance as a target of amylin's anti-carcinogenic function in GC. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that amylin exerted its oncogenic effects by inhibiting the PI3K/Akt signalling pathway (p < 0.05). CONCLUSIONS: Our findings demonstrate that amylin plays a crucial role in suppressing gastric cancer progression by targeting CCN1 and inhibiting the PI3K/Akt signalling pathway. These results suggest that amylin could serve as a potential therapeutic agent for GC treatment.

Humans↗

PubMed2026

Systematic Identification and Functional Characterisation of Colletotrichum fructicola Effectors During Camellia oleifera Colonisation.

Camellia oleifera is an important woody oil crop in southern China, but its production is severely threatened by anthracnose caused by Colletotrichum fructicola. C. fructicola deploys secreted effector proteins to establish infection. However, systematic identification and functional characterisation of C. fructicola effector genes upregulated during infection remains largely unexplored. Here, we integrated genome-wide secretome prediction with RNA-seq data from C. oleifera leaves inoculated with C. fructicola to identify candidate effectors induced during infection, followed by functional screening, targeted gene deletion, complementation and pathogenicity assays. Five novel effectors required for C. fructicola full virulence were identified, all of which suppressed Bax-induced cell death in Nicotiana benthamiana. Targeted deletion of the corresponding genes in C. fructicola reduced lesion areas by 47%-78% on C. oleifera leaves and by up to 67% on apple fruits, whereas complementation restored their virulence to wild-type levels. Transcriptomic profiling of infected postharvest C. oleifera fruits identified differentially expressed genes enriched in GO terms related to copper ion response, as well as in KEGG pathways associated with phenylpropanoid biosynthesis, taurine and hypotaurine metabolism, and plant-pathogen interactions. In addition, superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities, as well as malondialdehyde content, were altered in C. oleifera leaves inoculated with the effector-deletion mutants compared with those infected with the wild-type strain, suggesting that these effectors may contribute to the modulation of host oxidative stress responses. Taken together, our findings provide genetic and physiological evidence that these effectors contribute to C. fructicola virulence, offering potential targets for anthracnose control.

Colletotrichum↗

PubMed2026

Comparative Proteomic Analysis of the Striatum in Heterozygous and Null DAT Knockout Rats.

Deregulation of striatal neurotransmission is a key pathogenetic mechanism in neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism. In the present study, we applied a proteomic approach to demonstrate shifts in striatal protein expression in rats with heterozygous (DAT-Het) and homozygous (DAT-KO) dopamine transporter (DAT) gene knockouts. These animals model dose-dependent ADHD- and autism-like behaviors, ranging from slightly increased activity and social disturbances in DAT-Het rats to a pronounced phenotype in DAT-KO rats. We revealed pronounced changes in the proteomic profiles of both groups, associated primarily with deregulation of proteins involved in energy and carbon metabolism. Furthermore, we identified changes in vesicular transport proteins specific to DAT-KO and DAT-Het rats. Since these changes involved SNARE complex components, we evaluated SNARE mRNA expression in our models and public transcriptomic data for mouse models of neurodevelopmental disorders, including Mbd5 gene haploinsufficiency and a polygenic model of ADHD. No significant changes in mRNA levels were revealed in any model. Thus, the identified protein expression changes likely depend on post-transcriptional mechanisms. These data suggest a deregulation of metabolism in DAT-Het rats, which becomes more pronounced in DAT-KO rats.

Animals↗

PubMed2005

Postgenomic approach to identify novel Mycobacterium leprae antigens with potential to improve immunodiagnosis of infection.

Early detection of Mycobacterium leprae infection is considered an important component of strategies aiming at reducing transmission of infection, but currently available diagnostic tools often lack sufficient sensitivity and specificity to reach this goal. Recent comparative genomics have revealed the presence of 165 M. leprae genes with no homologue in M. tuberculosis. We selected 17 of these genes for further study. All 17 genes were found to be expressed at the mRNA level in M. leprae from infected mice and from a multibacillary leprosy patient. Additional comparative genomic analyses of all currently available mycobacterial genome databases confirmed 12 candidate genes to be unique to M. leprae, whereas 5 genes had homologues in mycobacteria other than M. tuberculosis. Evaluation of the immunogenicity of all 17 recombinant proteins in PBMC from 127 Brazilians showed that five antigens (ML0576, ML1989, ML1990, ML2283, and ML2567) induced significant gamma interferon levels in paucibacillary leprosy patients, reactional leprosy patients, and exposed healthy controls but not in most multibacillary leprosy patients, tuberculosis patients, or endemic controls. Importantly, among exposed healthy controls 71% had no detectable immunoglobulin M antibodies to the M. leprae-specific PGL-I but responded to one or more M. leprae antigen(s). Collectively, the M. leprae proteins identified are expressed at the transcriptome level and can efficiently activate T cells of M. leprae-exposed individuals. These proteins may provide new tools to develop tests for specific diagnosis of M. leprae infection and may enhance our understanding of leprosy and its transmission.

Animals↗

PubMed2004

Global gene expression in the immature brain after hypoxia-ischemia.

Ischemia induces a complex response of differentially expressed genes in the brain. In order to understand the specific mechanisms of injury in the developing brain, it is important to obtain information on global changes in the transcriptome after neonatal hypoxia-ischemia. In this study, oligonucleotide arrays were used to investigate genomic changes at 2, 8, 24, and 72 hours after neonatal hypoxia-ischemia, which was induced in 9-day-old mice by left carotid artery ligation followed by hypoxia (10% O2). In total, 343 genes were differentially expressed in cortex, hippocampus, thalamus, and striatum 2 to 72 hours after hypoxia-ischemia, when comparing ipsilateral with contralateral hemispheres and with controls, using the significance analysis for microarrays. A total of 283 genes were upregulated and 60 were downregulated, and 94% of the genes had not previously been shown after neonatal hypoxia-ischemia. Genes related to transcription factors and metabolism had mostly upregulated transcripts, whereas most downregulated genes belonged to the categories of ion and vesicular transport and signal transduction. Genes involved in transcription, stress, and apoptosis were induced early after the insult, and many new genes that may play important roles in the pathophysiology of neonatal hypoxia-ischemia were identified.

Aging↗

PubMed2025

Gfa1 (glutamine fructose-6-phosphate aminotransferase) is essential for Aspergillus fumigatus growth and virulence.

BACKGROUND: Aspergillus fumigatus, the primary etiological agent of invasive aspergillosis, causes over 1.8 million deaths annually. Targeting cell wall biosynthetic pathways offers a promising antifungal strategy. Gfa1, a rate-limiting enzyme in UDP-GlcNAc synthesis, plays a pivotal role in the hexosamine biosynthetic pathway (HBP). RESULTS: Deletion of gfa1 (Δgfa1) results in auxotrophy for glucosamine (GlcN) or N-acetylglucosamine (GlcNAc). Under full recovery (FR) conditions, where minimal medium is supplemented with 5 mM GlcN as the sole carbon source, the Δgfa1 mutant shows growth comparable to the wild-type (WT). However, when supplemented with 5 mM GlcN and 55 mM glucose, growth is partially repressed, likely due to carbon catabolite repression, a condition termed partial repression (PR). Under PR conditions, Δgfa1 exhibits compromised growth, reduced conidiation, defective germination, impaired cell wall integrity, and increased sensitivity to endoplasmic reticulum (ER) stress and high temperatures. Additionally, Δgfa1 demonstrates disruptions in protein homeostasis and iron metabolism. Transcriptomic analysis of the mutant under PR conditions reveals significant alterations in carbohydrate and amino acid metabolism, unfolded protein response (UPR) processes, and iron assimilation. Importantly, Gfa1 is essential for A. fumigatus virulence, as demonstrated in Caenorhabditis elegans and Galleria mellonella infection models. CONCLUSIONS: These findings underscore the critical role of Gfa1 in fungal pathogenicity and suggest its potential as a therapeutic target for combating A. fumigatus infections.

Aspergillus fumigatus↗

PubMed2006

DNA arrays as predictors of efficacy of adjuvant/neoadjuvant chemotherapy in breast cancer patients: current data and issues on study design.

Chemotherapy provides variable benefit to patients with breast cancer, with usually modest but occasionally severe side effects. Hence, there is a need to identify predictive biomarkers for its efficacy. DNA arrays have been used in this setting as potential novel predictive diagnostic tools. Several gene signatures and single gene markers were proposed to predict response to chemotherapy. Although this technology offers interesting perspectives through large-scale analysis of the transcriptome, its ability to identify clinically relevant predictors is highly dependent on study design. In the present manuscript, we will review currently available results of breast cancer pharmacogenomics and focus on aspects of study design that are critical to reliably identify predictive biomarkers using DNA array technology. We will discuss whether studies should be done in the overall, unselected breast cancer population or in specific homogeneous molecular subclasses. Next, we will compare advantages and limitations of cohort-based and case-control studies. The choice of end-point to discriminate between sensitive and resistant patients will also be examined.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Identity and effects of quorum-sensing inhibitors produced by Penicillium species.

Quorum sensing (QS) communication systems are thought to afford bacteria with a mechanism to strategically cause disease. One example is Pseudomonas aeruginosa, which infects immunocompromised individuals such as cystic fibrosis patients. The authors have previously documented that blockage of the QS systems not only attenuates Ps. aeruginosa but also renders biofilms highly susceptible to treatment with conventional antibiotics. Filamentous fungi produce a battery of secondary metabolites, some of which are already in clinical use as antimicrobial drugs. Fungi coexist with bacteria but lack active immune systems, so instead rely on chemical defence mechanisms. It was speculated that some of these secondary metabolites could interfere with bacterial QS communication. During a screening of 100 extracts from 50 Penicillium species, 33 were found to produce QS inhibitory (QSI) compounds. In two cases, patulin and penicillic acid were identified as being biologically active QSI compounds. Their effect on QS-controlled gene expression in Ps. aeruginosa was verified by DNA microarray transcriptomics. Similar to previously investigated QSI compounds, patulin was found to enhance biofilm susceptibility to tobramycin treatment. Ps. aeruginosa has developed QS-dependent mechanisms that block development of the oxidative burst in PMN neutrophils. Accordingly, when the bacteria were treated with either patulin or penicillic acid, the neutrophils became activated. In a mouse pulmonary infection model, Ps. aeruginosa was more rapidly cleared from the mice that were treated with patulin compared with the placebo group.

Animals↗

PubMed2025

Cellular imbalance in proximal and distal lung of CFTR-/- sheep in utero and at birth.

BACKGROUND: The Lung is the major focus of therapeutic approaches for the inherited disorder cystic fibrosis (CF) as without treatment lung disease is life-limiting. However, the initiating events that predispose the CF lung to cycles of infection, inflammation and resultant tissue damage are still unclear. Inflammation may occur in the CF lung prior to birth in human and several large animal models suggesting an in utero origin for the disease and encouraging further studies prior to birth. METHODS: Here we used the sheep model of CF (CFTR-/-) and age-matched wild-type (WT) sheep of the same breed to investigate the single cell transcriptomes of proximal and distal lung tissue at 80 days and 120 days of gestation and at term (147 days). Single cell RNA-seq was performed on tissues from 4 to 7 animals of each genotype (WT and CFTR-/-) at each time point. RESULTS: At term, FOXJ1-expressing ciliated cells are overrepresented in both lung regions from CFTR-/- lambs, while secretory epithelial and basal cells are underrepresented in proximal lung, as are T cells and monocytes in distal lung. The imbalance in ciliated and basal cells was confirmed by immunohistochemistry. At 120 days of gestation, lymphoid cells are slightly more abundant in proximal and distal lung from CFTR-/- animals compared to WT, consistent with the transient CF-associated inflammatory response in utero. At 80 days of gestation, T and B cells are underrepresented in both lung regions. CONCLUSIONS: The differences in epithelial cell abundance observed in the CFTR-/- lambs at term may reflect sequelae from the loss of CFTR on lung development and differentiation in utero. These findings provide novel insights into the cellular mechanisms of pathology and may be relevant to the design of new therapeutic approaches for CF lung disease.

Animals↗