Project description:Cholestatic injuries, featured with regional damage around the periportal, cause considerable mortality without curative therapies. It is technically challenging to dissect regional cell-cell interactions and molecular changes to fully understand cholangiopathies. Here, we generated a high-definition atlas of spatiotemporal transcriptome during cholestatic injury and repair. Remarkably, cholangiocytes functioned as a periportal hub by integrating signals from neighboring cells. We also dissected periportal damage, spatial heterogenous reprogramming and zonal regeneration, which appeared to be strongly associated with cholangiocyte. Moreover, spatiotemporal analyses revealed a key inhibitory rheostat for hepatocyte proliferation. Together, our study provides a comprehensive resource that is instrumental to demarcate regional cholestatic injury.
Project description:Transcription factors may orchestrate the health benefits of intermittent fasting through directing the expression of genome. Here, we find intermittent fasting can spin the spatiotemporal profile of transcription factors, and provide an atlas of transcription factors in biological space, time and feeding regimen.
Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases. Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu This study compares the injury and repair processed in wild-type mice after BDL.
Project description:To illuminate the evolutionary trajectory of LUAD from AIS to IAC, high-throughput scRNA-seq and ST data were generated and integrated to create a large-scale, single-cell spatiotemporal atlas of LUAD. We compiled a multi-omics atlas of the early-stage LUAD invasion process that reflects the heterogeneity of cancer cells, the competitive polyclonal origin of LUAD, signalling interactions between cancer cells and the TME, and the pseudo-chronological nature of LUAD invasion. The spatial distribution characteristics of LUAD cells revealed the spatial heterogeneity of LUAD and the mechanism of spatial immune escape in LUAD, which provides strong evidence supporting clinical diagnosis and surgical intervention at the single-cell level.
Project description:To illuminate the evolutionary trajectory of LUAD from AIS to IAC, high-throughput scRNA-seq and ST data were generated and integrated to create a large-scale, single-cell spatiotemporal atlas of LUAD. We compiled a multi-omics atlas of the early-stage LUAD invasion process that reflects the heterogeneity of cancer cells, the competitive polyclonal origin of LUAD, signalling interactions between cancer cells and the TME, and the pseudo-chronological nature of LUAD invasion. The spatial distribution characteristics of LUAD cells revealed the spatial heterogeneity of LUAD and the mechanism of spatial immune escape in LUAD, which provides strong evidence supporting clinical diagnosis and surgical intervention at the single-cell level. The seurat object of ST data are available on https://drive.google.com/drive/folders/1dkGF4kKMbHSm04DKHg6P_y_iTD1pXCH8?usp=sharing.
Project description:Cholestatic liver diseases are characterized by excessive accumulation of bile acids in the liver. The involvement of local tissue microenvironment in cholestatic diseases remains poorly understood. Here, we performed a comprehensive analysis of liver single-cell transcriptomic study of human cholestatic liver diseases. Our study involved 9 liver samples obtained from 7 patients diagnosed with hepatatrophia resulting from cholestasis. By utilizing single-cell data, we gained valuable insights into the specific functions of endothelial cells (EC) in response to chenodeoxycholic acid during cholestasis. The findings from our study hold the potential to lay the groundwork for personalized therapeutic approaches in the future, tailored to the individual needs of patients.
Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases.
Project description:In this study, using the mouse molar as a model, we took advantage of single-cell transcriptome profiling, lineage tracing and transgenic mouse models to interrogate the cellular heterogeneity and gene regulatory networks (GRNs) of postmigratory CNCCs.In this study, we have put together a dynamic spatiotemporal single-cell regulatory atlas and revealed the landscape of transcriptional heterogeneity and defined the cellular domains during the progression of cranial neural crest cell (CNCC)-derived dental lineage diversification. Importantly, we identified cell type-specific gene regulatory networks (GRNs) during CNCC-derived dental lineage development.
Project description:The human spinal cord contains diverse cell types, governed by a series of spatiotemporal events for tissue assembly and functions. However, the regulation of cell fate specification in the human developing spinal cord remains largely unknown. By performing single-cell and spatial multi-omics methods, we integrated the datasets and created a comprehensive human developmental atlas of the first trimester spinal cord. Unexpectedly, we discovered unique events in human spinal cord development, including early loss of active neural stem cells, simultaneous occurrence of neurogenesis and gliogenesis, and distinct spatiotemporal genetic regulations of fate choices. We also identified distinct regulations of cancer stem cells in ependymomas from our atlas. Thus, we demonstrate spatiotemporal genetic regulation of human spinal cord development and its potential to understand novel disease mechanisms.