Date of Award

Fall 8-31-2022

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Kristy Townsend

Second Committee Member

Thane Fremouw

Third Committee Member

Ashley Webb

Additional Committee Members

Martin Pera

Katherine Motyl

Abstract

Telomerase reverse transcriptase (TERT) is expressed by quiescent adult stem cells (qASC) in numerous adult murine and human tissues but has never been explored in the adult brain. Here, these data demonstrate that TERT+ cells in the adult mouse brain represent a novel population of multipotent qASCs. TERT+ cells were localized to numerous classical neuro/gliogenic niches including the ventricular-subventricular zone, hypothalamus and olfactory bulb, as well as newly discovered regions of adult tissue plasticity such as the meninges and choroid plexus. TERT+ cells expressed neural stem cell markers such as Nestin and Sox2, but not markers of activated stem/progenitor cells, nor markers of mature neuronal or glial cells. TERT+ qASCs also rarely expressed the proliferation marker Ki67, further confirming a quiescent phenotype. When cultured, TERT+ cells behaved like brain stem cells by forming proliferative neurospheres. Lineage tracing of TERT+ cells in adult transgenic mice revealed large-scale expansion of TERT+ progeny and differentiation in multiple brain regions to diverse cell types. Lineage-traced cells expressed markers of mature neurons, oligodendrocytes, astrocytes, ependymal cells, microglia, and choroid epithelial cells, thus demonstrating the striking multipotency of this stem cell population in basal tissue turnover. Finally, the neurogenic treatment of caloric restriction (CR) in lineage tracing animals revealed a decrease in TERT-traced cell

signal within the median eminence (ME) of the hypothalamus, with no change in the arcuate nucleus (ARC), when compared to unrestricted diet (UR)-treated animals. Single-cell RNA sequencing of TERT-traced cells in mice administered CR treatment also revealed an increase in the neuroprotective gene brain lipid binding protein (BLBP) in TERT-traced cells after 1 month of CR. As neuroprotection is a classical response to inflammation, we then studied the role of TERT+ cells in the inflammatory process of aging. TERT+ cell numbers varied with aging across neurogenic niches but remained a similar percentage of the full brain. However, TERT-traced cell signal increased significantly with aging, although label retention decreased. Together, these data demonstrate that TERT+ cells represent a new population of multipotent stem cells that contribute to basal brain plasticity and regeneration.

Comments

Embargo: Fall 2022 - Fall 2023

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