A characterization of the neural stem cell niche and lineage at single cell resolution during aging
Abstract/Contents
- Abstract
- The mammalian brain contains select neurogenic niches composed of neural stem cells (NSCs) and several other cell types, including microglia, and endothelial cells. Neurogenic niches become less functional with increasing age, and this decline could underlie cognitive and sensory deterioration. This functional deterioration could underlie cognitive and sensory restriction with age, although the exact age at which it occurs is still debated in humans. How the neurogenic niche changes with age, and whether new cell types arise in older individuals, is not known. Here we perform single cell RNA-sequencing of the young and old neurogenic niche in mice. We first show that cells in the youthful NSC lineage exist on a continuum through the processes of activation and differentiation. Interestingly, rare intermediate states with distinct molecular profiles can be identified and experimentally validated, and our analysis identifies putative surface markers and key intracellular regulators for these new subpopulations of NSCs. We also utilize the power of single cell profiling to conduct meta-analysis to compare in vivo NSCs and in vitro cultures, distinct fluorescent-activated cell sorting strategies, and different neurogenic niches. We go on to analyze the transcriptomes of 8993 single cells isolated in an unbiased fashion from the youthful and aged neurogenic niche. We identify clear age-dependent changes in the neurogenic niche, with a decrease in activated NSCs, changes in endothelial cells and microglia transcriptomes, and the striking appearance of T cells in old niches. T cells invading the old neurogenic niche exhibit characteristics of cytotoxic effector memory T cells. Surprisingly, T cells from old brains are clonally expanded, and express different T cell receptors than those from old blood, suggesting they experienced specific antigens. Furthermore, unlike their counterparts in old blood, old brain T cells express interferon γ (IFNγ) and immune checkpoint genes. Analysis of the response to IFNγ at the single cell level in the old neurogenic niche shows that several cell types, including NSCs, endothelial cells, and microglia, respond to IFNγ. The response of NSCs to IFNγ is heterogeneous, and the subset of NSCs experiencing a high IFN response shows decreased proliferation in vivo. Furthermore, IFNγ expressed by T cells was sufficient to inhibit NSC proliferation in co-cultures. Our study provides a system-level understanding of the old neurogenic niche and reveals the infiltration of T cells in old neurogenic niches. Our results also provide a possible cause for the decline of NSC during aging and could identify immune- or antigen-based strategies to ameliorate this decline.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Dulken, Benjamin William |
|---|---|
| Degree supervisor | Brunet, Anne, 1972- |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Palmer, Theo |
| Thesis advisor | Wyss-Coray, Anton |
| Degree committee member | Palmer, Theo |
| Degree committee member | Wyss-Coray, Anton |
| Associated with | Stanford University, Department of Stem Cell Biology and Regenerative Medicine. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Benjamin William Dulken. |
|---|---|
| Note | Submitted to the Department of Stem Cell Biology and Regenerative Medicine. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Benjamin William Dulken
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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