Project description:Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using Tff2-CreERT knockin mice, we identified highly proliferative Tff2+ progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2+ corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2+ progenitors abrogated SPEM formation, while genetic ablation of GIF+ chief cells enhanced SPEM formation from Tff2+ progenitors. In response to H. pylori infection, Tff2+ progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of KrasG12D mutations in Tff2+ progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional model of stepwise progression through metaplasia and instead identify Tff2+ progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.
Project description:The purpose of this experiment is to assess and characterize injury response of the gastric epithelial cells in trancriptomic level. Pgc+ epithelial cells (excluding parietal cells and enteroendocrine cells) were isolated from the mouse gastric corpus without injury or at 1d after DMP777-mediated acute injury.
Project description:The purpose of this experiment is to assess and characterize injury response of the gastric chief cells in trancriptomic level. Gif lineage cells (TdTom- GFP+) from Gif-rtTA; TetO-Cre; Rosa-mTmG mice line after Dox administration were isolated from the mouse gastric corpus without injury or at 2d after DMP777-mediated acute injury.
Project description:Purpose: The central nervous system (CNS) possesses intrinsic remyelination capabilities in response to demyelinating injury. However, this remyelination potential is diminished as demyelinating disease such as multiple sclerosis progresses overtime. To better understand myelin repair processes, the goal of this study was to determine temporal transcriptomic changes in cerebral white matter (corpus callosum) and gray matter (cortex and hippocampus) after acute and chronic demyelinating injury. The cuprizone mouse model of de- and remyelination was used for this investigation. Methods: Adult C57BL/6 mice were exposed to cuprizone diet (0.2%) for 3, 5 or 12 weeks followed by returning to normal diet for up to 12 weeks for recovery. Brain regions were dissected for bulk RNA-seq. Conclusion: RNA-seq analyses suggest common and distinct spatiotemporal transcriptional alterations during CNS demyelination and remyelination. Dataset for this study represents the first that covers gene expression landscapes of three brain regions over extended regenerative periods after chronic CNS demyelination.
Project description:Compared to whole serum miRNAs, miRNAs in serum small extracellular vesicles (sEVs) are well protected form RNA enzymes, thus provide a consistent source of miRNA for disease biomarker detection. Serum sEVs and their miRNA cargos released by injured liver cells could be promising biomarkers for diagnosis of liver diseases. We were very interested to find out the effects of liver injury on serum extracellular vesicles as well as the small RNA components they transported, if there is any difference between acute and chronic injury. Study in this regard will help us to identify new serum biomarkers for liver injury, and to find out if there are specific markers for acute or chronic liver injury. To identify potential biomarker for liver injury based on serum sEVs miRNAs, we established the carbon tetrachloride (CCL4) induced acute and chronic liver injury mice model, and examined the dynamic changes of small RNA components, especially miRNAs, in serum sEVs.
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.