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Wu, D.

Publications and source records attributed to Wu, D..

At least 199 records · Page 11Linked to original sources
bioRxiv2023

Lack of Fzd6 in Ciliated Cells Suppresses Ferroptotic Pulmonary Alveolar Cell Death Induced by LPS and Coronavirus

Pulmonary inflammation compromises lung barrier function and underlies many lung diseases including acute lung injury and acute respiratory distress syndrome (ARDS). However, mechanisms by which lung cells respond to the damage caused by the inflammatory insults are not completely understood. Here we show that Fzd6-deficiency in Foxj1+ ciliated cells reduces pulmonary permeability, lipid peroxidation, and alveolar cell death accompanied with an increase in alveolar number in lungs insulted by LPS or a mouse coronavirus. Single-cell RNA sequencing of lung cells indicates that the lack of Fzd6, which is expressed in Foxj1+ cells, increases expression of the aldo-keto reductase Akr1b8 in Foxj1+ cells. Intratracheal administration of the Akr1b8 protein phenocopies Fzd6-deficient lung phenotypes. In addition, ferroptosis inhibitors also phenocopy Fzd6-deficient lung phenotypes and exert no further effects in Fzd6-deficient lungs. These results reveal an important mechanism for protection of alveolar cells from ferroptotic death during pulmonary inflammation by Foxj1+ ciliated cells via paracrine action of Akr1b8.

pathology↗
bioRxiv2023

Histone acetylation insulator SET orchestrates PP2A inhibition and super-enhancer activation

Wide-spread growth-essential genes are hyper-transcribed in the pancreatic cancer cells. Searching for the factors that reprogram this abnormal transcription, we identified the nuclear oncogene SET that supported CDK9-induced and Pol II-mediated transcription. SET disrupted PP2A-A/C interaction via its C-terminal domains. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Meanwhile, as a histone acetylation insulator, SET mainly suppressed histone acetylation in the gene promoters but evaded enhancers. Massive super-enhancer associated genes, including the oncogene MET, were hence permitted to be transcribed by SET over-expression. Our findings position SET as a key factor that bridges histone acetylation and PP2A related transcription in cancer cells.

molecular biology↗
bioRxiv2022

Epigenetic reprogramming shapes the cellular landscape of schwannoma

Cell state evolution underlies tumor development and response to therapy1, but mechanisms specifying cancer cell states and intratumor heterogeneity are incompletely understood. Schwannomas are the most common tumors of the peripheral nervous system and are treated with surgery and ionizing radiation2-5. Schwannomas can oscillate in size for many years after radiotherapy6,7, suggesting treatment may reprogram schwannoma cells or the tumor microenvironment. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas. We find schwannomas are comprised of 2 molecular groups distinguished by reactivation of neural crest development pathways or misactivation of nerve injury mechanisms that specify cancer cell states and the architecture of the tumor immune microenvironment. Schwannoma molecular groups can arise independently, but ionizing radiation is sufficient for epigenetic reprogramming of neural crest to immune-enriched schwannoma by remodeling chromatin accessibility, gene expression, and metabolism to drive schwannoma cell state evolution and immune cell infiltration. To define functional genomic mechanisms underlying epigenetic reprograming of schwannomas, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of cancer evolution and establish a paradigm of epigenetic reprograming of cancer in response to radiotherapy.

cancer biology↗
bioRxiv2022

Spatial-temporal evolution characteristics of land use and its driving factor analysis during the period of 2000-2020 in Putian City, Fujian Province

Exploring the spatial and temporal evolution characteristics of land use and its driving force can provide scientific basis for the construction of regional ecological civilization. Based on the remote sensing cloud computing platform of Google Earth Engine (GEE), the study took the remote sensing images of the three periods of 2000, 2010 and 2020 as the basic data and interpreted them to obtain the basic land use data of Putian city and its five districts and counties. The land-use change characteristics of Putian city in those periods were systematically analyzed by using the methods of single land-use dynamics and Geo-informatic Tupu, so as to reveal the Tupu characteristics of land-use transfer and the spatial-temporal evolution pattern in the past 20 years. Then social and economic development indicators were selected to further explore the key driving force of land-use evolution in the study area by canonical correspondence analysis. The results showed that: 1) the land use structure of Putian city was mainly composed of cultivated land and forest land, and the other land types were embedded in them and the built-up land continued to expand outward. 2) The spatial distribution of Tupu units of land use transfer in Putian city was significantly different, change types of land use were diversified and the areas of cultivated land and grassland transferred out were the most obvious. Different degrees of cultivated land abandonment had occurred in various regions. Putian city was facing great challenges in ensuring food security and curbing the non-agricultural and non grain of cultivated land. 3) The macro-economic development in a specific period, especially the urban expansion and the development of the secondary industry caused by the merger of cities and counties, were the key factors driving the spatial and temporal evolution of land use and the differential distribution pattern in Putian city. The author suggested that land resources should be used efficiently in addition to optimizing the layout of land use and carrying out the renovation of abandoned land. Therefore, the study proposed to strengthen the scientific planning and effective regulation of land use, combine spatial and temporal resources of cultivated land with agriculture, culture and tourism, and build ecological barriers and ecological corridors to ensure the coordinated and sustainable development of regional ecology and economy.

ecology↗
bioRxiv2022

Multi-modal multi-resolution atlas of the human neonatal cerebral cortex based on microstructural similarity

The neonatal period is a critical window for the development of the human brain and may hold implications for the long-term development of cognition and disorders. Multi-modal connectome studies have revealed many important findings underlying the adult brain but related studies were rare in the early human brain. One potential challenge is the lack of an appropriate and unbiased parcellation that combines structural and functional information in this population. Using 348 multi-modal MRI datasets from the developing human connectome project, we found that the information fused from the structural, diffusion, and functional MRI was relatively stable across MRI features and showed high reproducibility at the group level. Therefore, we generated automated multi-resolution parcellations (300 - 500 parcels) based on the similarity across multi-modal features using a gradient-based parcellation algorithm. In addition, to acquire a parcellation with high interpretability, we provided a manually delineated parcellation (210 parcels), which was approximately symmetric, and the adjacent areas around each boundary were statistically different in terms of the integrated similarity metric and at least one kind of original features. Overall, the present study provided multi-resolution and neonate-specific parcellations of the cerebral cortex based on multi-modal MRI properties, which may facilitate future studies of the human connectome in the early development period.

neuroscience↗
bioRxiv2022

Differential Expression Analysis for Metatranscriptomics with Sample-Paired Metagenomics Data

1MotivationLarge microbial communities have contributed to essential ecosystems and multiple health and disease processes. Metatranscriptomics (MTX) is becoming increasingly important for profiling the gene expression pattern and functional activities of microbial communities. A fundamental task for analyzing the high-throughput sequencing data is the Differential Expression (DE) analysis, which aims to identify up/down-regulated genes/pathways across multiple conditions. However, DE analysis is complicated by the variation of underlying DNA copies, which is caused by the highly dynamic nature of microbial communities. The non-independent change between MTX and MGX may lead to false discoveries about which genes are biologically differentially expressed. Nevertheless, We can settle this problem by using the information from paired metagenomics (MGX) data. ResultsWe proposed the MetaDePair, a statistical model for DE analysis in MTX with paired MGX data. It relied on a conditional Negative-Binomial distribution to model the count data. We showed that the adjustment of underlying DNA copies could significantly eliminate the variations of RNA data, thus improving the power of statistical inference. Also, we found that appropriate pre-filtering of zeros can also improve the sensitivity and precision of the model. Moreover, we proposed a method to simulate the paired MTX and MGX data. Using simulated data and real microbial data sets, we demonstrated that our method has a high statistical power while controlling the false discovery rate (FDR). We applied the tool to oral microbiome data and identified significant genes that are associated with Early Childhood Caries (ECC). Our tool enabled a more accurate and effective DE analysis based on MTX with paired MGX data and helped us improve the understanding of the functional characterization of microbial communities.

genomics↗
bioRxiv2022

Transcription factor TFAP2C affects porcine early embryo development via regulating epigenetic modification

Transcription factors (TFs) have the potential function in regulating gene expression. Transcription factor TFAP2C plays important roles in the regulation of post-implantation embryonic development in mice, the reprogramming process, trophectoderm formation and carcinogenesis, but its role in porcine early embryo development remains unclear. This study was conducted to investigate the role of TFAP2C in porcine early embryo development using siRNA cytoplasmic injection. The RNAseq and immunofluorescence staining were performed to detect gene expression, and ChIP and dual luciferase reporter assays were used to elucidate the mechanism. The results showed that the deficiency of TFAP2C could lead to embryonic development disorder. The percentage of the blastocyst in the TFAP2C knockdown (TFAP2C-KD) group (7.76{+/-}1.86%) was significantly decreased compared to the control group (22.92{+/-}1.97%) (P**<0.01). The RNAseq results showed that 1208 genes were downregulated and 792 genes were upregulated after siRNA injection. The expression of epigenetic modification enzymes KDM5B, SETD2 (P**<0.01) etc. were significantly elevated in TFAP2C-KD group. Meanwhile, the modification levels of H3K4me3, H3K4me2 and H3K9me3 (P*<0.05) were significantly decreased, and the modification levels of H3K36me3 (P**<0.01) and DNA methylation (P**<0.01) were significantly increased in TFAP2C-KD group. DNMT1 was mostly expressed in cytoplasm in the control group, while it was mainly expressed in nuclei in the TFAP2C-KD group. In addition, TFAP2C could bind to the promoter region of SETD2, and the mutation of the TFAP2C binding site resulted in increased activity of SETD2 promoter (P**<0.01). The knockdown of TFAP2C affects histone modification and DNA methylation by regulating the expression of SETD2, KDM5B etc. and other genes, thereby inhibiting embryonic development. TFAP2C binds to the promoter region of SETD2 and acts as a hindrance protein. This study fills in the deficiency of TFAP2C in porcine early embryo development and provides theoretical support for animal husbandry production and biomedicine. Author SummaryThe correct activation of embryonic genes is required during early embryonic development, and the activation of these genes is subject to strict epigenetic regulation, such as DNA methylation, histone acetylation and methylation, with abnormalities in either leading to birth defects and developmental defects in individuals. TFs have specific binding motifs that regulate gene expression by binding to them. TFAP2C has been studied in post-implantation embryonic development and trophectoderm generation, however, the effect on early embryo development is unknown. Our findings suggest that TFAP2C deficiency disrupts gene expression patterns and leads to abnormal epigenetic modifications, resulting in abnormal embryo development. Furthermore, we found for the first time that TFAP2C can bind to the promoter region of SETD2, thereby affecting early embryo development in pigs. This indicates the critical role of TFAP2C in early embryo development in pigs on one hand, and also provides theoretical support for livestock production and biomedicine.

developmental biology↗
bioRxiv2022

Cryo-EM Structure of the 50S-HflX Complex Reveals a Novel Mechanism of Antibiotic Resistance in E. coli

Bacterial HflX is a conserved ribosome-binding GTPase involved in splitting ribosomal complexes accumulated under stress condition. However, the atomic details of its ribosomal interaction remain to be elucidated. In this work, we present a high-resolution structure of the E. coli 50S subunit bound with HflX. The structure reveals highly specific contacts between HflX and the ribosomal RNA, and in particular, an insertion loop of the N-terminal domain of HflX is situated in the peptidyl transferase center (PTC) and makes direct interactions with PTC residues. Interestingly, this loop displays steric clash with a few PTC-targeting antibiotics on the 50S subunit, such as chloramphenicol. Deletion of hflX results in hypersensitivity to chloramphenicol treatment, and a loop residue G154 of HflX is important for the observed chloramphenicol resistance. Overall, our results suggest that HflX could be a general stress response factor that functions in both stalled ribosome splitting and PTC antibiotic displacing.

cell biology↗
bioRxiv2022

The Cul5 E3 Ligase Complex Is a Key Negative Feedback Regulator of TCR/IL2 Signaling and Anti-Tumor Activity in CD8+ T Cells

CD8+ T cells play an important role in tumor immune surveillance and control. Better understanding of the regulation of their anti-tumor actions and improving their cytotoxic function and persistence will help advancing cancer immunotherapies. Here, we report the development of a step-wise CRISPR knockout (KO) screening strategy under the selection of TGF-{beta}, a clinically relevant immunosuppressive pressure. The screen identifies Cul5 as a negative-feedback regulator of the core signaling pathways, differentiation, and persistence of CD8+ T cell. Cul5 KO in mouse CD8+ T cells significantly improves their tumor control ability in vitro and in vivo with significant proteomic alterations that generally enhance TCR and cytokine signaling, effector function, stemness, and survival of CD8+ T cell. Mechanistically, Cul5, whose protein content and active, neddylated form increase upon TCR-stimulation, interacts with SOCS-box-containing Pcmtd2 and negatively regulates TCR and IL2/STAT5 signaling by decreasing TCR and IL2 signaling molecules. Moreover, Cul5 KO in human CD8+ T cells phenocopies that in mouse CD8+ T cells. Furthermore, KO of CTLA4 that is markedly upregulated by Cul5 KO in mouse and human CD8+ cells further enhances anti-tumor effect of Cul5 KO, and a neddylation inhibitor enhances CD8 effector activities largely dependently of Cul5. These results together not only reveal a previously unknown negative-feedback regulatory mechanism for CD8+ T cells, but also have strong translational implications in cancer immunotherapy.

immunology↗
bioRxiv2022

Efficient Multi-Label Attribute Classification and Recognition of Microbiological Bacteria Based on Deep Learning and model fine-tuning

Bacterial vaginosis (BV) is the most common gynecological complaint affecting health of a large percentage of women worldwide. Traditional manual microscopy methods are expensive and time-consuming, to improve accuracy and efficiency, automated bacterial identification devices with detection intelligence algorithms are urgently needed. We propose a Fine-tuned SmallerVGG (FTS-VGG) deep convolutional network model based multi-label classification method for bacteria. Comparison experiments were deployed on several advanced backbone networks, including transfer learning on pre-trained VGG19, demonstrating that the proposed method achieves the advantages of being lighter, faster, more accurate and more efficient. Due to the high cost of time and expertise of experienced clinicians, we use random erasing for data augmentation to address the challenge of dataset collection and annotation, experiments demonstrate its robustness to occlusion. The proposed method has theoretical and practical implications, as well as the potential to be widely extended to other microscopic imaging applications.

biochemistry↗
bioRxiv2022

Identification and structural modeling of the chlamydial RNA polymerase omega subunit

Gene transcription in bacteria is carried out by the multisubunit RNA polymerase (RNAP), which is composed of a catalytic core enzyme and a promoter-recognizing {sigma} factor. RNAP core enzyme comprises two subunits, one {beta} subunit, one {beta} s subunit, and one {omega} (omega) subunit. Across multiple bacterial taxa, the RNAP {omega} subunit plays critical roles in the assembly of RNAP core enzyme and in other cellular functions, including regulation of bacterial growth, stress response, and biofilm formation. However, for several intracellular bacterium, including the obligate intracellular bacterium Chlamydia, no RNAP {omega} subunit previously has been identified. Here, we report the identification of Chlamydia trachomatis hypothetical protein CTL0286 as the chlamydial RNAP {omega} ortholog, based on sequence, synteny, and AlphaFold and AlphaFold-Multimer three-dimensional-structure predictions. We conclude that CTL0286 functions as the previously missing chlamydial {omega} ortholog. Extensions of our analysis indicate that all obligate intracellular bacteria have {omega} orthologs. IMPORTANCEChlamydiae are common mammalian pathogens. Chlamydiae have a unique developmental cycle characterized with an infectious but nondividing elementary body (EB), which can temporarily survive outside host cells, and a noninfectious reticulate body (RB), which replicates only intracellularly. Chlamydial development inside host cells can be arrested during persistence in response to adverse environmental conditions. Transcription plays a central role in the progression of the chlamydial developmental cycle as well as entry into and recovery from persistence. The identification of the elusive {omega} subunit of chlamydial RNAP makes possible future study of its regulatory roles in gene expression during chlamydial growth, development, and stress responses. This discovery also paves the way to prepare and study the intact chlamydial RNAP and its interactions with inhibitors in vitro.

molecular biology↗
bioRxiv2022

Leveraging prior biological knowledge improves prediction of tocochromanols in maize grain

With an essential role in human health, tocochromanols are mostly obtained by consuming seed oils; however, the vitamin E content of the most abundant tocochromanols in maize grain is low. Several large-effect genes with cis-acting variants affecting mRNA expression are mostly responsible for tocochromanol variation in maize grain, with other relevant associated quantitative trait loci (QTL) yet to be fully resolved. Leveraging existing genomic and transcriptomic information for maize inbreds could improve prediction when selecting for higher vitamin E content. Here, we first evaluated a multikernel genomic best linear unbiased prediction (MK-GBLUP) approach for modeling known QTL in the prediction of nine tocochromanol grain phenotypes (12-21 QTL per trait) within and between two panels of 1,462 and 242 maize inbred lines. On average, MK-GBLUP models improved predictive abilities by 7.0 to 13.6% when compared to GBLUP. In a second approach with a subset of 545 lines from the larger panel, the highest average improvement in predictive ability relative to GBLUP was achieved with a multi-trait GBLUP model (15.4%) that had a tocochromanol phenotype and transcript abundances in developing grain for a few large-effect candidate causal genes (1-3 genes per trait) as multiple response variables. Taken together, our study illustrates the enhancement of prediction models when informed by existing biological knowledge pertaining to QTL and candidate causal genes. Core IdeasO_LIWith varying levels of vitamin E activity, tocochromanols found in maize grain are essential for human health C_LIO_LISelecting for higher vitamin E content in maize grain can be enhanced with genomic prediction C_LIO_LIPrediction models leveraging existing biological knowledge were evaluated in two panels of maize inbred lines C_LIO_LIMultikernel prediction models based on previously identified QTL improved predictive ability C_LIO_LIA multi-trait prediction model that had transcript abundances of a few large-effect causal genes performed the best C_LI

genetics↗
bioRxiv2022

Molecular basis for antiviral activity of pediatric neutralizing antibodies targeting SARS-CoV-2 Spike receptor binding domain

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV- 2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC-evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

microbiology↗
bioRxiv2022

Gabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified "tethering elements" (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular 2{delta}1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and 2{delta}1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between 2{delta}1 and PLN domains and demonstrated for the first time that 2{delta}1 strongly associates with PLN via its domain III. Furthermore, 2{delta}1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::2{delta}1 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and 2{delta}1, necessary for bone force transmission and sensitive to the drug GBP. This work provides insights into the mechanisms underlying mechanotransduction and will inform future studies to understand the mechanisms responsible for the negative effects of GBP on bone.

molecular biology↗
bioRxiv2022

Metformin Alleviates Arthrofibrosis in Rat via Fibroblast Metabolic Reprogramming and Lactate-Mediated Macrophage Polarization

BackgroundEmerging studies have suggested an essential role of fibroblast metabolic reprogramming in the pathogenesis of arthrofibrosis. The metabolic modulator metformin appears to be a therapeutic candidate for fibrotic disorders. However, whether metformin could alleviate arthrofibrosis has not been defined. In this study we have determined if treatment with metformin has the beneficial effect on arthrofibrosis and its underlying mechanism. MethodsArticular capsule samples were collected from patients with/without arthrofibrosis to perform gene and protein expression analysis. Arthrofibrosis animal model was established to examine the anti-fibrotic effect of metformin. Cell culture experiments were conducted to determine the mechanism by which metformin inhibits fibroblast activation. ResultsWe found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated inflammatory reactions, downregulated expression of both fibrotic and glycolytic markers, improved range of motion of the joint, and reduced capsular fibrosis and thickening. At the cellular level, metformin inhibited the activation of fibroblasts and mitigated the abundant influx of glucose into activated fibroblasts. Interestingly, metformin prompted a metabolic shift from oxidative phosphorylation to aerobic glycolysis in activated fibroblasts, resulting in the anti-fibrotic effect of metformin. ConclusionMetformin decreased glycolysis, causing a metabolic shift toward aerobic glycolysis in activated fibroblasts and has beneficial effect on the treatment of arthrofibrosis. The translational potential of this articleThe finding of this study demonstrated the therapeutic effect of metformin on arthrofibrosis and defined novel targets for the treatment of articular fibrotic disorders.

cell biology↗
bioRxiv2022

Pan-cancer analysis reveals the value of FDX1 as a novel biomarker in the prognosis and immunotherapy in human tumors

Emerging evidence supports FDX1s important role in the development and progression of cancer, but no extensive cancer analysis is available to date. This study was the first to comprehensively explore the expression of FDX1 in 33 types of cancer and the significance of FDX1 in clinical prognosis by using bioinformatics techniques. Meanwhile, we analyzed the relationship between FDX1 and pathological stage, as well as immune cell infiltration. Based on this, the important role of FDX1 in tumor immunotherapy was proposed. The expression of FDX1 was significantly different between normal and tumor samples in 17 of 33 types of cancer. Besides, Cox regression analysis showed that FDX1 is a protective gene in Kidney renal clear cell carcinoma (KIRC), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Liver hepatocellular carcinoma (LIHC), Kidney renal papillary cell carcinoma (KIRP), Mesothelioma (MESO), and Thyroid carcinoma (THCA). Porphyrin and oxidative metabolism pathway regulating integrator complex was involved in the process. Furthermore, high expression of FDX1 promoted infiltration of Eosinophils and monocyte in Adrenocortical carcinoma (ACC) and Kidney Chromophobe (KICH) by affecting the tumor microenvironment (TME) and was significantly correlated with immune checkpoint genes. Our first pan-cancer analysis elucidates the expression characteristics of FDX1 across different cancers and highlights its potential value as a prognostic biomarker, laying a foundation for further study of its immunotherapy mechanism in various cancers.

bioinformatics↗
bioRxiv2022

Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co- stimulation in a mice acute-on-chronic liver failure model

Boosting stem cell resilience against an extrinsically harsh recipient environment is critical to therapeutic efficiency of stem cell-based transplantation innovations in liver disease contexts. We aimed to establish the efficacy of a transient plasmid-based preconditioning strategy to boost mesenchymal stromal cells (MSCs) capacity for anti-inflammation/antioxidant defense and paracrine actions on recipient hepatocytes. In MSCs, the master antioxidant regulator Nrf2 was found to bind directly to the antioxidant response element in the DKK1 promoter region. Activation of Nrf2 and DKK1 enhanced the anti-stress capacities of MSCs in vitro. In an acute-on-chronic liver failure (ACLF) murine model, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection markedly improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy and promoted recipient liver regeneration because of a shift from the activation of the anti-regenerative IFN-{gamma}/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Moreover, specific ablation of DKK1 receptor CKAP4 but not LRP6 in recipient hepatocytes nullified therapeutic benefits from MSC transplantation. In long-term observations, tumorigenicity was undetected in mice following transplantation of such transiently preconditioned MCSs. In conclusion, co-stimulation of Nrf2/DKK1 signaling decisively and safely improves the efficacy of human MSC-based therapies in mouse ACLF models through apparently CKAP4-dependent paracrine mechanisms.

molecular biology↗