Project description:Progenitor cells play fundamental roles in preserving optimal organismal functions under normal, aging, and disease conditions. However, progenitor cells are incompletely characterized, especially in the brain, partly because conventional methods are restricted by inadequate throughput and resolution for deciphering cell-type-specific proliferation and differentiation dynamics in vivo. Here, we developed TrackerSci, a new technique that combines in vivo labeling of newborn cells with single-cell combinatorial indexing to profile the single-cell chromatin landscape and transcriptome of rare progenitor cells and track cellular differentiation trajectories in vivo. We applied TrackerSci to analyze the epigenetic and gene expression dynamics of newborn cells across entire mouse brains spanning three age stages and in a mouse model of Alzheimer's disease. Leveraging the dataset, we identified diverse progenitor cell types less-characterized in conventional single cell analysis, and recovered their unique epigenetic signatures. We further quantified the cell-type-specific proliferation and differentiation potentials of progenitor cells, and identified the molecular programs underlying their aging-associated changes (e.g., reduced neurogenesis/oligodendrogenesis). Finally, we expanded our analysis to study progenitor cells in the aged human brain through profiling ~800,000 single-cell transcriptomes across five anatomical regions from six aged human brains. We further explored the transcriptome signatures that are shared or divergent between human and mouse oligodendrogenesis, as well as the region-specific down-regulation of oligodendrogenesis in the human cerebellum. Together, the data provide an in-depth view of rare progenitor cells in mammalian brains. We anticipate TrackerSci will be broadly applicable to characterize cell-type-specific temporal dynamics in diverse systems.
Project description:Progenitor cells are critical in preserving organismal homeostasis, yet their diversity and dynamics in the aged brain remain underexplored. We introduced TrackerSci, a single-cell genomic method that combines newborn cell labeling and combinatorial indexing to characterize the transcriptome and chromatin landscape of proliferating progenitor cells in vivo. Using TrackerSci, we investigated the dynamics of newborn cells in mouse brains across various ages and in a mouse model of Alzheimer's disease. Our dataset revealed diverse progenitor cell types in the brain and their epigenetic signatures. We further quantified aging-associated shifts in cell-type-specific proliferation and differentiation and deciphered the associated molecular programs. Extending our study to the progenitor cells in the aged human brain, we identified conserved genetic signatures across species and pinpointed region-specific cellular dynamics, such as the reduced oligodendrogenesis in the cerebellum. We anticipate that TrackerSci will be broadly applicable to unveil cell-type-specific temporal dynamics in diverse systems.
Project description:Stanford type A aortic dissection (STAAD) is an aortic degenerative remodeling disease carrying an exceedingly high mortality worldwide. The irreversible weakening, dilatation and dissection of the ascending aorta contributes to circulatory failure and premature death. Dissections manifest distinct patterns in both clinical presentations and histophathological features during disease temporal transition. Therefore, we delineate a full repertoire of cellular landscape and dynamic interplay in distinct temporal patterns of STAAD using single-cell transcriptomics for comprehensively understanding of disease features and temporal evolution. We performed single-cell RNA sequencing with ascending aortic tissues from 14 participants, including 9 patients with STAAD (4 acute, 3 subacute, and 2 chronic) and 5 control subjects. Unsupervised clustering was performed based on transcriptional profiles of highly variable genes. Single T cell analysis by RNA sequencing and TCR tracking (STARTRACT) was performed to quantitatively delineate the developmental trajectory of aortic T lymphocytes. On the basis of molecular signatures and distinct disease patterns, we draw a spatiotemporal map of disease subtype-specific alterations and complex interplay among cell types. The transcriptional profiles of 93,397 individual cells enable us to identify 12 major cell types and 37 subtypes in human ascending aorta. Comparisons of transcriptomes of disease subtypes reveal striking stage-specific cellular diversity and transcriptional dynamics in phenotypic switch, vascular inflammation, cell death and survival, extracellular matrix remodeling, and cell-cell interactions during disease temporal transition. Modeling of developmental trajectory revealed that the defects in mitochondrial OXPHOS drives phenotypic switch of contractile smooth muscle cells to synthetic myofibroblasts through AP-1 transcriptional complex. STARTRACT analysis revealed that CD8+ HSP are preferentially enriched and potentially clonally expanded in acute AD. Intersection of disease risk genes with our dataset reveals distinct gene panel in discriminating temporal-specifc AD. This compendium of transcriptome data provides valuable insights and a rich resource for understanding the cellular diversity and heterogeneity in human aorta. The distinct alterations of cell type- and disease subtype-specific spatiotemporal features will ultimately facilitate the design of more precisely tailored anti-AD therapies.
Project description:The emergence of the hematopoietic system occurs in temporal waves across different tissues during mouse development. During these waves, the endothelial niche serves as a source of hematopoietic cells and provides molecular cues that potentially shape the tissue-specific lineage output. Although the endothelial-to-hematopoietic transition in the aorta-gonad-mesonephros is well understood, a systematic analysis of hematopoietic progenitors and their endothelial niche across fetal tissues is lacking. Here, we leverage single-cell RNA-sequencing of micro-dissected fetal tissues during their peak of hematopoietic activity to systematically compare hematopoietic progenitors and the endothelial niche. We predict stage-specific interactions accompanying the transition of yolk sac endothelium to primitive and definitive hematopoietic fates and reveal distinct roles for fetal liver vascular niches. Furthermore, we provide in vitro evidence that lipid signaling by sphingosine-1-phosphate producing erythrocyte progenitors supports hematopoietic stem cell expansion in fetal liver. Our resource deciphers the temporal waves of hematopoietic development within distinct vascular niches.
Project description:In this study, we attempted to identify the heterogeneity and temporal dynamics of leukocytes at single-cell level in mouse heart after inducing MI using the longitudinal single-cell RNA sequencing and spatial transcriptome sequencing.