Bromodeoxyuridine induces senescence in neural stem and progenitor cells.
Bromodeoxyuridine induces senescence in neural stem and progenitor cells.
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DOI：
10.1634/stemcells.2008-0299
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Laywell ED
中科院分区：
文献类型：
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作者：
Ross HH;Levkoff LH;Marshall GP 2nd;Caldeira M;Steindler DA;Reynolds BA;Laywell ED
溴脱氧尿苷（BrdU）是一种卤代嘧啶，在S期掺入新合成的DNA中。BrdU广泛用于细胞出生日期研究，并作为测量各种细胞群增殖指数的手段。在没有次级应激源的情况下，BrdU被认为相对良性地掺入复制DNA链中。然而，我们在这里报告说，一个单一的，低剂量的BrdU脉冲产生深远的和持续的抗增殖作用，在培养的小鼠干细胞和祖细胞。这伴随着改变的终末分化，细胞形态和蛋白质表达与衰老的诱导一致。没有证据表明自发性细胞死亡显著增加;然而，细胞对化学诱导的细胞凋亡具有抗性。最后，我们表明，一个简短的体内BrdU方案降低了随后分离的室管膜下区神经球形成细胞的增殖潜力。因此，我们得出结论，BrdU治疗诱导衰老途径，导致快速分裂的干/祖细胞的复制进行性下降，这表明BrdU的一种新的和未表征的效果。这一发现是重要的，BrdU掺入神经干/祖细胞和他们的后代不应该预期正常的行为方面的增殖潜力和下游功能参数。这种效应凸显了在解释基于多轮复制的长期BrdU追踪的结果时需要谨慎。相反，可靠的诱导干/祖细胞在体外和体内衰老可能会产生一个新的平台，旨在解决衰老和神经发生的多个方面的分子研究。
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.