Tracking Temporal Dynamics in Human and Mouse Brain Cell Types

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Summary

In this study, researchers unveiled TrackerSci, an innovative single-cell genomic tool, to delve into the complexity of progenitor cells in the brain, particularly focusing on aging and Alzheimer's disease in mice. This cutting-edge method melds cell labeling with combinatorial indexing, allowing an in-depth analysis of these cells' transcriptomes and chromatin landscapes. Their findings shed light on a variety of progenitor cell types and their unique epigenetic patterns, unraveling age-related changes in proliferation and differentiation, as well as their molecular underpinnings. The study extended to aged human brains, revealing cross-species genetic similarities and distinct regional cell dynamics, like diminished oligodendrogenesis in the cerebellum. TrackerSci's potential for broader applications in understanding cell-specific temporal dynamics is significant.

Fig.1 Graphical abstract¹.

Research Criteria

This article delves into analyzing the variety and behavior of brain progenitor cells, especially as they relate to aging. It highlights the development of TrackerSci, an innovative approach combining new cell labeling with combinatorial indexing. This technique is pivotal in examining the transcriptome and chromatin environment of these actively dividing cells within a living organism.

Fig.2 Experimental design¹.

Sample Type

Cells from mouse and human brains.

Result—Global View of Newborn Cells across Mammalian Brain by TrackerSci

TrackerSci, an innovative method for analyzing rare proliferating cells in the mammalian brain, marks cells with EdU and employs a two-step sorting process to isolate these cells, crucial for studying aged brains where such cells are less than 0.1% of the total. This technique, integrating sci-RNA-seq and sci-ATAC-seq, maintains the molecular state of cells, as evidenced by its alignment with standard profiling. Applied to mice across various life stages and genotypes, including Alzheimer's disease models, TrackerSci provided detailed transcriptomic and chromatin accessibility profiles, particularly highlighting progenitor cells' prevalence in EdU-positive populations compared to general brain cells. Its integration with a global brain cell atlas revealed continuous cellular differentiation trajectories, demonstrating its utility in uncovering complex cellular dynamics in adult brain tissues.

Fig.3 TrackerSci provides single-cell transcriptome and chromatin accessibility profiling of mammalian brain growing cells¹.

Result—Impact of Aging on Adult Brain Cell Growth

This study investigated the effects of aging on adult neurogenesis, identifying three key neurogenesis trajectories. Using TrackerSci profiling, the researchers validated these pathways and, through differential gene expression analysis, identified thousands of genes involved, some shared and others unique to specific neuron types. Chromatin accessibility profiling revealed dynamic patterns in numerous sites and transcription factors, highlighting the complex genetic and epigenetic interplay. The research showed a notable age-dependent reduction in progenitor cell density, with genes showing concordant changes over time, including neurotrophic factors and neurogenesis regulators. Validation with a genome-wide CRISPR screen confirmed the impact of these genes on neurogenesis in aged neural stem cells. The study also examined the role of telomere-maintenance pathways in neurogenesis, revealing significant changes in cell proliferation and differentiation with aging.

Fig.4 Identifying the effects of aging on neurogenesis¹.

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Reference

1. Lu, Ziyu, et al. "Tracking cell-type-specific temporal dynamics in human and mouse brains." Cell 186.20 (2023): 4345-4364.