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Bromodeoxyuridine induces senescence in neural stem and progenitor cells.

ABSTRACT: Bromodeoxyuridine (BrdU) is a halogenated pyrimidine that incorporates into newly synthesized DNA during the S phase. BrdU is used ubiquitously in cell birthdating studies and as a means of measuring the proliferative index of various cell populations. In the absence of secondary stressors, BrdU is thought to incorporate relatively benignly into replicating DNA chains. However, we report here that a single, low-dose pulse of BrdU exerts a profound and sustained antiproliferative effect in cultured murine stem and progenitor cells. This is accompanied by altered terminal differentiation, cell morphology, and protein expression consistent with the induction of senescence. There is no evidence of a significant increase in spontaneous cell death; however, cells are rendered resistant to chemically induced apoptosis. Finally, we show that a brief in vivo BrdU regimen reduces the proliferative potential of subsequently isolated subependymal zone neurosphere-forming cells. We conclude, therefore, that BrdU treatment induces a senescence pathway that causes a progressive decline in the replication of rapidly dividing stem/progenitor cells, suggesting a novel and uncharacterized effect of BrdU. This finding is significant in that BrdU-incorporating neural stem/progenitor cells and their progeny should not be expected to behave normally with respect to proliferative potential and downstream functional parameters. This effect highlights the need for caution when results based on long-term BrdU tracking over multiple rounds of replication are interpreted. Conversely, the reliable induction of senescence in stem/progenitor cells in vitro and in vivo may yield a novel platform for molecular studies designed to address multiple aspects of aging and neurogenesis.

SUBMITTER: Ross HH

PROVIDER: S-EPMC4541772 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Bromodeoxyuridine induces senescence in neural stem and progenitor cells.

Ross Heather H HH Levkoff Lindsay H LH Marshall Gregory P GP Caldeira Maria M Steindler Dennis A DA Reynolds Brent A BA Laywell Eric D ED

Stem cells (Dayton, Ohio) 20080918 12

Bromodeoxyuridine (BrdU) is a halogenated pyrimidine that incorporates into newly synthesized DNA during the S phase. BrdU is used ubiquitously in cell birthdating studies and as a means of measuring the proliferative index of various cell populations. In the absence of secondary stressors, BrdU is thought to incorporate relatively benignly into replicating DNA chains. However, we report here that a single, low-dose pulse of BrdU exerts a profound and sustained antiproliferative effect in cultur ...[more]

PMID: 18802036

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Project description:While irradiation can effectively treat brain tumors, this therapy also causes cognitive impairments, some of which may stem from the disruption of hippocampal neurogenesis. To study how radiation affects neurogenesis, we combine phenotyping of subpopulations of hippocampal neural stem and progenitor cells with double- and triple S-phase labeling paradigms. Using this approach, we reveal new features of division, survival, and differentiation of neural stem and progenitor cells after exposure to gamma radiation. We show that dividing neural stem cells, while susceptible to damage induced by gamma rays, are less vulnerable than their rapidly amplifying progeny. We also show that dividing stem and progenitor cells that survive irradiation are suppressed in their ability to replicate 0.5-1 day after the radiation exposure. Suppression of division is also observed for cells that entered the cell cycle after irradiation or were not in the S phase at the time of exposure. Determining the longer term effects of irradiation, we found that 2 months after exposure, radiation-induced suppression of division is partially relieved for both stem and progenitor cells, without evidence for compensatory symmetric divisions as a means to restore the normal level of neurogenesis. By that time, most mature young neurons, born 2-4 weeks after the irradiation, still bear the consequences of radiation exposure, unlike younger neurons undergoing early stages of differentiation without overt signs of deficient maturation. Later, 6 months after an exposure to 5 Gy, cell proliferation and neurogenesis are further impaired, though neural stem cells are still available in the niche, and their pool is preserved. Our results indicate that various subpopulations of stem and progenitor cells in the adult hippocampus have different susceptibility to gamma radiation, and that neurogenesis, even after a temporary restoration, is impaired in the long term after exposure to gamma rays. Our study provides a framework for investigating critical issues of neural stem cell maintenance, aging, interaction with their microenvironment, and post-irradiation therapy.

Dataset Information

Bromodeoxyuridine induces senescence in neural stem and progenitor cells.

Publications

Bromodeoxyuridine induces senescence in neural stem and progenitor cells.

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