Project description:In vivo differentiation of human pluripotent stem cells (hPSCs) has unique advantages such as multilineage differentiation, angiogenesis, and close cell‒cell interactions. To systematically investigate the multilineage differentiation mechanisms of hPSCs, we constructed the in vivo hPSC differentiation landscape containing 239,670 cells using teratoma models. We inferred 18 cell differentiation trajectories and characterized common and specific gene regulation patterns during hPSC differentiation at both transcriptional and epigenetic levels. The results of developing single cell Basic Local Alignment Search Tool (dscBLAST), our self-developed tool for cell identification and developmental stage speculation, further confirmed the differentiated cell identity and suggested that cells in the teratoma are largely at immature developmental stages. Overall, our study offers new insights into stem cell fate decisions and embryonic development; dscBLAST shows favorable cell identification performance, providing both developmental and adult cells with a powerful tool for cell annotation and stage speculation.
Project description:In vivo differentiation of human pluripotent stem cells (hPSCs) has unique advantages, such as multilineage differentiation, angiogenesis, and close cell-cell interactions. To systematically investigate multilineage differentiation mechanisms of hPSCs, we constructed the in vivo hPSC differentiation landscape containing 239,670 cells using teratoma models. We identified 43 cell types, inferred 18 cell differentiation trajectories, and characterized common and specific gene regulation patterns during hPSC differentiation at both transcriptional and epigenetic levels. Additionally, we developed the developmental single-cell Basic Local Alignment Search Tool (dscBLAST), an R-based cell identification tool, to simplify the identification processes of developmental cells. Using dscBLAST, we aligned cells in multiple differentiation models to normally developing cells to further understand their differentiation states. Overall, our study offers new insights into stem cell differentiation and human embryonic development; dscBLAST shows favorable cell identification performance, providing a powerful identification tool for developmental cells.
Project description:(scRNA and scATAC) in profiling non-myocytes (non-CMs) from young, middle-aged, and elderly mice. Non-CMs, vital in heart development, physiology, and pathology, are understudied compared to cardiomyocytes. Our analysis revealed aging response heterogeneity and its dynamics over time among non-CM cell types. Immune cells, notably macrophages and neutrophils, showed significant aging alterations, while endothelial cells displayed moderate changes. We identified distinct aging signatures within the cell type, including differential gene expression and transcription factor activity, along with motif variation. Sub-cluster analysis revealed intra-cell type heterogeneity, characterized by diverse aging patterns. The senescence-associated secretory phenotype (SASP) emerged as a key aging-related phenotype. Moreover, aging significantly influenced cell-cell communication, especially impacting a fibroblast sub-cluster with high expression of Erbb4. This study elucidates the complex cellular and molecular landscape of cardiac aging in non-CMs, highlighting their importance in cardiac aging and offering guidance for future potential therapeutic avenues to treat aging-related heart diseases.
Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
Project description:In vivo differentiation of human pluripotent stem cells (hPSCs) has unique advantages such as multilineage differentiation, angiogenesis, and close cell‒cell interactions. To systematically investigate the multilineage differentiation mechanisms of hPSCs, we constructed the in vivo hPSC differentiation landscape containing 239,670 cells using teratoma models. We inferred 18 cell differentiation trajectories and characterized common and specific gene regulation patterns during hPSC differentiation at both transcriptional and epigenetic levels. The results of developing single cell Basic Local Alignment Search Tool (dscBLAST), our self-developed tool for cell identification and developmental stage speculation, further confirmed the differentiated cell identity and suggested that cells in the teratoma are largely at immature developmental stages. Overall, our study offers new insights into stem cell fate decisions and embryonic development; dscBLAST shows favorable cell identification performance, providing both developmental and adult cells with a powerful tool for cell annotation and stage speculation.