Biology subjects

Chen, P.

Publications and source records attributed to Chen, P..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-{gamma} and TNF stimulated lung macrophages to chronically release IL-1{beta}, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-{gamma} and TNF, or IL-1{beta} after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

immunology↗

bioRxiv2023

Functional connectome through the human life span

The lifespan growth of the functional connectome remains unknown. Here, we assemble task-free functional and structural magnetic resonance imaging data from 33,250 individuals aged 32 postmenstrual weeks to 80 years from 132 global sites. We report critical inflection points in the nonlinear growth curves of the global mean and variance of the connectome, peaking in the late fourth and late third decades of life, respectively. After constructing a fine-grained, lifespan-wide suite of system-level brain atlases, we show distinct maturation timelines for functional segregation within different systems. Lifespan growth of regional connectivity is organized along a primary-to-association cortical axis. These connectome-based normative models reveal substantial individual heterogeneities in functional brain networks in patients with autism spectrum disorder, major depressive disorder, and Alzheimers disease. These findings elucidate the lifespan evolution of the functional connectome and can serve as a normative reference for quantifying individual variation in development, aging, and neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

Fungal-bacteria interactions provide shelter for bacteria in Caesarean section scar diverticulum

Caesarean section scar diverticulum (CSD) is a significant cause of infertility among women who have previously had a Caesarean section, primarily due to persistent inflammatory exudation associated with this condition. Even though abnormal bacterial composition is identified as a critical factor leading to this chronic inflammation, clinical data suggests that a long-term cure is often unattainable with antibiotic treatment alone. In our study, we employed metagenomic analysis and mass spectrometry techniques to investigate the fungal composition in CSD and its interaction with bacteria. We discovered that local fungal abnormalities in CSD can disrupt the stability of the bacterial population and the entire microbial community by altering bacterial abundance via specific metabolites. For instance, Lachnellula suecica reduces the abundance of several Lactobacillus spp., such as Lactobacillus jensenii, by diminishing the production of metabolites like Goyaglycoside A and Janthitrem E. Concurrently, Clavispora lusitaniae and Ophiocordyceps australis can synergistically impact the abundance of Lactobacillus spp. by modulating metabolite abundance. Our findings underscore that abnormal fungal composition and activity are key drivers of local bacterial dysbiosis in CSD.

microbiology↗

bioRxiv2023

Estimating foraging behavior in rodents using a modified paradigm measuring threat imminence dynamics

Animals display defensive behaviors in response to threats to avoid danger and approach rewards. In nature, these responses did not evolve alone but are always accompanied by motivational conflict. A semi-naturalistic threat imminence continuum model models the approach-avoidance conflict and is able to integrate multiple defensive behaviors into a single paradigm. However, its comprehensive application is hampered by the lack of a detailed protocol and data about some fundamental factors including sex, age, and motivational level. Here, we modified a previously established paradigm measuring threat imminence continuum dynamics, involving modifications of training and testing protocols, and utilization of commercial materials combined with open science codes, making it more standardized and easier to replicate. We demonstrate that foraging behavior is modulated by age, hunger level, and sex. This paradigm can be used to study defensive behaviors in animals in a more naturalistic manner with relevance to human approach-avoid conflicts and associated psychopathologies. HighlightsO_LIWe provide detailed guidance for setting up a modified paradigm for the threat imminence continuum model with commercial materials and open-source codes. C_LIO_LIWe propose a modified paradigm for the threat imminence continuum model to quantify foraging behaviors. C_LIO_LIOur method enables comparison between groups as a function of multiple factors including age and food restriction. C_LI Graphic Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/550314v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@f4be92org.highwire.dtl.DTLVardef@b7f6dorg.highwire.dtl.DTLVardef@db0dc1org.highwire.dtl.DTLVardef@1640cce_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2023

Induction of plant disease resistance by mixed oligosaccharide elicitors prepared from plant cell wall and crustacean shells

Basal plant immune responses are activated by the recognition of the conserved pathogen-associated molecular patterns (PAMPs), or breakdown molecules released from plants after damage by pathogen infection, so-called danger-associated molecular patterns (DAMPs). While chitin-oligosaccharide (CHOS), a primary component of the fungal cell wall, is most known as PAMP, plant cell wall-derived oligosaccharides, cello-oligosaccharides (COS) from cellulose and xylo-oligosaccharide (XOS) from hemicellulose, are representative DAMPs, which activate signaling steps similar to PAMP-induced immunity to elicit defenses and provide protection against pathogens. In this study, elicitor activities of COS prepared from cotton linters, XOS prepared from corn cobs as well as chitin-oligosaccharide (CHOS) from crustacean shells were comparatively investigated. In Arabidopsis, treatment of COS, XOS or CHOS triggered typical defense responses such as reactive oxygen species (ROS) production, activation of MAP kinases phosphorylation, callose depositions, and activation of the promoter for defense-related transcription factor WRKY33. When COS, XOS and CHOS were used at concentrations with similar activity in inducing ROS production and callose depositions, CHOS was particularly highly potent in activating the MAPK kinases and WRKY33 promoters. Among the COS and XOS with different degrees of polymerization (DP), cellotriose (DP3) and xylotetraose (DP4) showed the highest activity for the activation of WRKY33 promoter. Simultaneous treatment of COS, XOS and CHOS leads to a strong transcriptional change for defense-related genes, and gene ontology (GO) enrichment analysis of RNAseq data revealed that a mixture of three oligosaccharide (oligo-mix) effectively activate the plants disease resistance. In practice, treatment of the oligo-mix enhanced the resistance of tomato to powdery mildew, but plant growth was not inhibited but rather tended to be promoted, providing evidence that mixed oligosaccharides have beneficial effects on improving disease resistance in plants, making them a promising class of compounds for practical application.

plant biology↗

bioRxiv2023

Estimating Insulin Sensitivity and Beta-Cell Function from the Oral Glucose Tolerance Test: Validation of a new Insulin Sensitivity and Secretion (ISS) Model

Efficient and accurate methods to estimate insulin sensitivity (SI) and beta-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes. Many methods exist, ranging in input data and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic models (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new ISS (Insulin Secretion and Sensitivity) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. The model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. The model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including post-challenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts including individuals at high risk of prediabetes (adult women with a wide range of BMI and adolescents with obesity). The new model had strong correlation with gold-standard estimates from intravenous glucose tolerance tests and hyperinsulinemic-euglycemic clamp. The ISS model has broad clinical applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.

physiology↗

bioRxiv2023

Disease associated human TCR characterization by deep-learning framework TCR-DeepInsight

T cell function is defined by both T cell receptors (TCR) and T cell gene expression (GEX). Although single-cell technology enables the simultaneous capture of TCR and GEX information, the lack of a reference atlas and computational tools hinders our ability to uncover the fundamental TCR usage rules and to efficiently characterize disease-associated TCRs (dTCR). Here, through the collection of million-scale single-cell GEX-TCR reference atlas comprising 20 diverse disease conditions, we revealed the intrinsic features of TCR-MHC (Major Histocompatibility Complex) restriction in CD4/CD8 lineages. We observed the higher coherence for TCR/{beta} chains in memory T cells, and detected widely-existing public TCR/{beta} pairs across individuals. Building upon the reference atlas, we introduced TCR- DeepInsight, a deep-learning framework featuring a disease specificity scoring system that enables the characterization of dTCR clusters with similar GEX-TCR. Our study provides a valuable tool for researchers to analyze single-cell GEX-TCR data and identify dTCRs comprehensively and robustly.

bioinformatics↗

bioRxiv2023

Neuregulin-1 protects against respiratory viral induced mortality

Respiratory viral infections due to RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen similar to RSV, Sendai virus (SeV), we found that mice made atopic with house dust mite before viral infection all survived a normally lethal SeV infection. Moreover, adoptive transfer of CD11c+ cells from atopic mice delayed viral mortality. Neuregulin-1 (NRG1) message was highly expressed in CD11c+ cells from atopic mice and atopic lungs and bronchoalveolar lavage fluid had elevated levels of NRG1 protein. Administration of NRG1 protected non-atopic mice from death and associated with reduced alveolar epithelium permeability. Utilizing an in vitro system of well-differentiated human bronchial epithelial cells and mouse tracheal epithelial cells NRG1 reduced RSV and SeV titers. Expression of genes that play a role in airway epithelium integrity and stability were altered by NRG1; potentially regulating viral induced dysregulation of the epithelia and suggesting NRG1 mediated maintenance of homeostasis. In conclusion, our studies demonstrate atopy induced NRG1 likely plays a novel role in survival from severe respiratory viral infections and may have therapeutic value to prevent mortality from these infections. SignificanceSevere respiratory viral infections are associated with significant mortality in infants and the elderly; however, allergic disease can protect from these outcomes. This study identified a protein called neuregulin-1 (NRG1), produced by cells of the immune system in allergic mice, that provides a survival advantage against respiratory viral infection. NRG1 pretreatment in non-atopic mice infected with a lethal dose of a rodent RNA virus (Sendai virus), similar to human respiratory syncytial virus, significantly reduced death. Further, NRG1 pretreatment reduced viral replication in human and mouse airway epithelial cell cultures. These studies signify a potential therapeutic role of NRG1 in modulating the severity of respiratory viral infections.

immunology↗

bioRxiv2023

Nuclear growth and import can be uncoupled

What drives nuclear growth? Studying nuclei assembled in Xenopus egg extract and focusing on importin /{beta}-mediated nuclear import, we show that, while nuclear growth depends on nuclear import, nuclear growth and import can be uncoupled. Nuclei containing fragmented DNA grew slowly despite exhibiting normal import rates, suggesting nuclear import itself is insufficient to drive nuclear growth. Nuclei containing more DNA grew larger but imported more slowly. Altering chromatin modifications caused nuclei to grow less while still importing to the same extent or to grow larger without increasing nuclear import. Increasing heterochromatin in vivo in sea urchin embryos increased nuclear growth but not import. These data suggest that nuclear import is not the primary driving force for nuclear growth. Instead, live imaging showed that nuclear growth preferentially occurred at sites of high chromatin density and lamin addition, whereas small nuclei lacking DNA exhibited less lamin incorporation. Our hypothesized model is that lamin incorporation and nuclear growth are driven by chromatin mechanical properties, which depend on and can be tuned by nuclear import.

cell biology↗

bioRxiv2023

Amoeboid cells undergo durotaxis with soft end polarized NMIIA

Cell migration towards stiff substrates has been coined as durotaxis and implicated in development, wound healing and cancer, where complex interplays between immune and non-immune cells are present. Compared to the emerging mechanisms underlying the strongly adhesive mesenchymal durotaxis, little is known about whether immune cells - migrating in amoeboid mode - could follow mechanical cues. Here we develop an imaging-based confined migration device with stiffness gradient. By tracking live cell trajectory and analyzing the directionality of T cells and neutrophils, we observe that amoeboid cells can durotax. We further delineate the underlying mechanism to involve non-muscle myosin IIA (NMIIA) polarization towards the soft-matrix-side but may not require differential actin flow up- or down-stiffness gradient. Using the protista Dictyostelium, we demonstrate the evolutionary conservation of amoeboid durotaxis. Finally, these experimental phenomena are theoretically captured by an active gel model capable of mechanosensing. Collectively, these results may shed new lights on immune surveillance and recently identified confined migration of cancer cells, within the mechanically inhomogeneous tumor microenvironment or the inflamed fibrotic tissues.

cell biology↗

bioRxiv2023

Clostridium butyricum and Clostridium tyrobutyricum: angle or devil for Necrotizing enterocolitis?

BackgroundNecrotizing enterocolitis (NEC), high incidence and case-fatality rate among premature neonates, is a frustrating gastrointestinal disease which hard to eradicate currently for its unclear pathogenesis and mechanisms. What has been conformed is that the gut microbes dysbiosis happens before the occurrence of NEC, providing robust evidence for the usage of probiotic therapy. Hence, we mainly concentrated on two probiotics: Clostridium butyricum and Clostridium tyrobutyricum especially after the breakthrough in discovering that several clostridia species have associations with NEC. ResultTo verify whether these two clostridia are pathogenic or probiotic, we compared the phenotypic traits of NEC mice treated with two clostridia. Our results proof that treatment with C. tyrobutyricum recovers the intestinal barrier integrity and alleviates inflammatory immune response of NEC, while treatment with C. butyricum aggrevates the intestinal barrier damage and promotes immune disorder including the number of macrophages, monocytes and neutrophils in Intestinal lamina propria. Further analysis of gut micrbiome implies that the positive effect of C. tyrobutyricum treatment is in association with the increase of Akkermansia muciniphila. Meanwhile, C. butyricum treatment decreases the level of A. muciniphila, which accounts for the negative effect to NEC. ConclusionThis study sheds light on that treatment with C. tyrobutyricum but not C. butyricum is entitled to protect against NEC development potentially. The mechanisms behind the opposite effect on NEC may result in different modulation on the level of A. muciniphila, which is deeply associated with intestinal homoeostasis. Briefly, through improving the abundance of A. muciniphila to alleviate intestinal inflammation and enhance intestinal barrier integrity, C. tyrobutyricum supplement may become a promising therapy for NEC.

microbiology↗

bioRxiv2023

High-Throughput Bioprinting of the Nasal Epithelium using Patient-derived Nasal Epithelial Cells

Human nasal epithelial cells (hNECs) are an essential cell source for the reconstruction of the respiratory pseudostratified columnar epithelium composed of multiple cell types in the context of infection studies and disease modeling. Hitherto, manual seeding has been the dominant method for creating nasal epithelial tissue models. However, the manual approach is slow, low-throughput and has limitations in terms of achieving the intricate 3D structure of the natural nasal epithelium in a uniform manner. 3D Bioprinting has been utilized to reconstruct various epithelial tissue models, such as cutaneous, intestinal, alveolar, and bronchial epithelium, but there has been no attempt to use of 3D bioprinting technologies for reconstruction of the nasal epithelium. In this study, for the first time, we demonstrate the reconstruction of the nasal epithelium with the use of primary hNECs deposited on Transwell inserts via droplet-based bioprinting (DBB), which enabled high-throughput fabrication of the nasal epithelium in Transwell inserts of 24-well plates. DBB of nasal progenitor cells ranging from one-tenth to one-half of the cell seeding density employed during the conventional cell seeding approach enabled a high degree of differentiation with the presence of cilia and tight-junctions over a 4-week air-liquid interface culture. Single cell RNA sequencing of these cultures identified five major epithelial cells populations, including basal, suprabasal, goblet, club, and ciliated cells. These cultures recapitulated the pseudostratified columnar epithelial architecture present in the native nasal epithelium and were permissive to respiratory virus infection. These results denote the potential of 3D bioprinting for high-throughput fabrication of nasal epithelial tissue models not only for infection studies but also for other purposes such as disease modeling, immunological studies, and drug screening.

bioengineering↗

bioRxiv2023

Terrestrial Support of Aquatic Food Webs via an Overlooked Pathway-Inorganic Carbon and its Significance to Global Carbon Cycle

Freshwater ecosystems receive substantial terrestrial organic matter (t-OM) from surrounding landscapes. How the t-OM is transferred affects aquatic food webs and global carbon budgets. Previous studies have emphasized terrestrial support of aquatic ecosystems via direct organic carbon subsidy, overlooking the dissolved inorganic carbon (DIC) pathway, that is, DIC from t-OM decomposition is used by aquatic primary producers, supporting higher trophic levels. Using 2-year 13C and 15N measurements of phytoplankton, zooplankton, terrestrial plants, sediments, dissolved and particulate organic matter from seasonal wetlands, we found that while zooplankton (mid-trophic consumers) used t-OM directly in January, in March and May zooplankton were mainly supported by phytoplankton that used DIC recycled from t-OM mineralization and methanogenesis. The dominance of this DIC pathway is tightly coupled with the characteristics of these systems. Mineralization and methanogenesis of rich fresh t-OM resulted in supersaturated CO2 with high CO2 and CH4 emissions. Atmospheric CO2 diffusion and methanogenesis significantly enriched{delta} 13C of DIC, leading to wide variations in{delta} 13C of DIC between -12.4 and 6.7 {per thousand}, which provided ideal conditions to quantify carbon cycling in these widespread but understudied ecosystems. Our findings draw attention to potentially high carbon emissions from temporary freshwater ecosystems that are being increasingly common under warming climate.

ecology↗

bioRxiv2023

Single-cell mRNA-regulation analysis reveals cell type-specific mechanisms of type 2 diabetes

Perturbed secretion of insulin and other pancreatic islet hormones is the main cause of type 2 diabetes (T2D). The islets harbor five cell types that are potentially altered differently by T2D. Whole-islet transcriptomics and single-cell RNA-sequencing (scRNAseq) studies have revealed differentially expressed genes without reaching consensus. Here, we demonstrate that unprecedented insights into disease mechanisms can be obtained by network-based analysis of scRNAseq data. We developed differential gene coordination network analysis (dGCNA) and analyzed islet scRNAseq data from 16 T2D and 16 non-T2D individuals. dGCNA revealed T2D-induced cell type-specific networks of dysregulated genes with remarkable ontological specificity, thus allowing for a comprehensive and unbiased functional classification of genes involved in T2D. In beta cells eleven networks of genes were detected, revealing that mitochondrial electron transport chain, glycolysis, cytoskeleton organization, cell proliferation, unfolded protein response and three networks of beta cell transcription factors are perturbed, whereas exocytosis, lysosomal regulation and insulin translation programs are instead enhanced in T2D. Furthermore, we validated the ability of dGCNA to reveal disease mechanisms and predict the functional context of genes by showing that TMEM176A/B regulates the beta cell cytoskeleton and that CEPBG is a key regulator of the unfolded protein response. In addition, comparing beta- and alpha and cells, we found substantial differences, reproduced across independent datasets, confirming cell type-specific alterations in T2D. We conclude that analysis of networks of differentially coordinated genes provides outstanding insight into cell type-specific gene function and T2D pathophysiology.

cell biology↗

bioRxiv2023

Expansion microscopy with trypsin digestion and tyramide signal amplification (TT-ExM) for protein and lipid staining

Expansion microscopy, whereby the relative positions of biomolecules are physically increased via hydrogel expansion, can be used to reveal ultrafine structures of cells under a conventional microscope. Despite its utility for achieving super-resolution imaging, expansion microscopy suffers two major drawbacks, namely proteolysis and swelling effects that, respectively, induce protein loss and dilute fluorescence signals. Here, we report two improvements to expansion microscopy that overcome these two challenges, i.e., deploying trypsin digestion to reduce protein loss and tyramide signal amplification to enhance fluorescence signal. We name our new methodology TT-ExM to indicate dual trypsin and tyramide treatments. TT-ExM may be applied for both antibody and lipid staining. Notably, we demonstrate better protein retention for endoplasmic reticulum and mitochondrial markers in COS-7 cell cultures following 2-h trypsin treatment. Subsequent lipid staining revealed the complex 3D membrane structures in entire cells. Through combined lipid and DNA staining, our TT-ExM methodology highlighted mitochondria by revealing their DNA and membrane structures in cytoplasm, as well as the lipid-rich structures formed via phase separation in nuclei at interphase. We also observed lipid-rich chromosome matrices in the mitotic cells. Thus, TT-ExM significantly enhances fluorescent signals and generates high-quality and ultrafine-resolution images under confocal microscopy.

cell biology↗

bioRxiv2023

Transcriptomic analysis of diverse organisms reveals the rareness of genetic assimilation in environmental adaptations

Genetic assimilation is the evolutionary process by which an environmentally induced phenotype becomes genetically encoded and constitutive. Genetic assimilation has been proposed as the concluding step in the plasticity-first model of environmental adaptation and has been observed in multiple species, but its prevalence has not been systematically investigated. By analyzing transcriptomic data collected upon reciprocal transplant, we address this question in the experimental evolution, domestication, or natural evolution of a bacterial, a fungal, a plant, and four animal species. We find that genetic assimilation of environment-induced gene expression is the exception rather than the rule and that substantially more genes retain than lose their expression plasticity upon organismal adaptations to new environments. The probability of genetic assimilation varies among genes and decreases with the number of transcription factors controlling the gene and the expression level of the gene, supporting the hypothesis that genetic assimilation results primarily from passive losses of gene regulations that are not mutationally robust. Therefore, at the level of gene expression, our findings argue against the purported importance of genetic assimilation to environmental adaptation.

evolutionary biology↗

bioRxiv2022

Fibroblasts-derived extracellular vesicles contain SFRP1 and mediate pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a lethal and chronic lung disease characterized by aberrant intercellular communication, increased extracellular matrix (ECM) deposition, and destruction of functional lung tissue. Extracellular vesicles (EVs) accumulate within the lung in IPF, but their cargo and biological effects remain unclear. Here, we provide the entire the proteome of EV and non-EV fraction during pulmonary fibrosis, and functionally characterize their contribution to fibrosis. EVs were isolated by differential ultracentrifugation of bronchoalveolar lavage fluid (BALF) collected from mice challenged with bleomycin (or PBS as control) or culture supernatants from primary mouse lung fibroblasts. EVs were characterized by nanoparticle tracking analysis, Western Blotting, and quantitative mass spectrometry to define their proteome. EVs accumulation peaked at 14 days post-bleomycin instillation and correlated with decreased lung function. Label-free proteomics identified 107 proteins specific to fibrotic BALF-EVs. This signature was associated with wound healing, extracellular matrix organization, and cell motility. BALF-EVs from fibrotic lungs promoted fibrogenesis, including induction of ECM proteins in precision cut lung slices ex vivo and impaired alveolar epithelial cell stem cell function. Deconvolution using single cell RNA sequencing datasets revealed that fibroblasts are the major cellular source of BALF-EVs. EVs from fibroblasts were significantly enriched in Secreted Frizzled Related Protein 1 (SFRP1). In the lungs of patients with IPF, SFRP1 was significantly increased in mesenchymal cells. Sfrp1 deficiency reduced the ability of fibroblast-derived EVs to potentiate bleomycin-induced lung fibrosis in vivo and led to a reduction in fibrosis marker gene expression. In sum, EVs carry specific protein cargos, such as SFRP1, to contribute to organ remodeling during fibrosis. Our data identified EVs transporting SFRP1 as a potential therapeutic target for IPF.

cell biology↗

bioRxiv2022

STING-dependent cytosolic DNA sensing pathway drives the progression to leukemia in TET2-mutated HSPCs

Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain largely unknown. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in leukemogenesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn induces the development of CH and myeloid transformation. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant myelopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the hematopoietic transformation associated with TET2 mutations is powered through sterile inflammation dependent on the activated cGAS-STING pathway, and that STING may represent a potential target for intervention of relevant hematopoietic malignancies. Key pointsO_LITet2 deficiency leads to DNA damage which in turn activates the cGAS-STING pathway to induce an inflammatory response C_LIO_LIBlocking STING in TET2-mutated hematopoietic stem/progenitor cells suppresses clonal hematopoiesis in mice and leukemogenesis in patient-derived xenograft models C_LI

cancer biology↗