Hematopoietic stem cell ageing is uncoupled from p16INK4A-mediated senescence
Hematopoietic stem cell ageing is uncoupled from p16INK4A-mediated senescence
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DOI：
10.1038/onc.2009.94
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发表时间：
2009-06-01
期刊：
影响因子：
8
通讯作者：
Bryder, D.
中科院分区：
文献类型：
--
作者：
Attema, J. L.;Pronk, C. J. H.;Bryder, D.
体细胞干细胞最终负责调节适当的器官稳态，因此被认为是衰老过程的细胞起源，这种状态通常以不适当的稳态为特征。具体而言，已经表明，衰老的干细胞可能屈服于复制衰老的机制涉及细胞周期蛋白依赖性激酶抑制剂p16（INK 4A）。在这里，我们测试了多个功能和分子参数指示p16（INK 4A）活性在原代老化小鼠造血干细胞（HSC）。我们发现没有证据表明复制性衰老伴随着体内干细胞衰老，并且与p16（INK 4A）是这种过程的关键决定因素一致，大多数老化的HSC（>99%）未能在mRNA水平表达p16（INK 4A）。此外，尽管INK 4A/ARF基因座的表观遗传学引导的抑制的丧失伴随着复制性衰老的鼠胚胎成纤维细胞，但这种抑制在衰老的干细胞中得以维持。总之，这些研究表明，由p16（INK 4A）肿瘤抑制因子介导的衰老增加仅作为体内稳态HSC衰老的内在调节因子发挥次要作用。Oncogene（2009）28，2238-2243; doi：10.1038/onc.2009.94; 2009年4月27日在线发表
Somatic stem cells are ultimately responsible for mediating appropriate organ homeostasis and have therefore been proposed to represent a cellular origin of the ageing process-a state often characterized by inappropriate homeostasis. Specifically, it has been suggested that ageing stem cells might succumb to replicative senescence by a mechanism involving the cyclin-dependent kinase inhibitor p16(INK4A). Here, we tested multiple functional and molecular parameters indicative of p16(INK4A) activity in primary aged murine hematopoietic stem cells (HSCs). We found no evidence that replicative senescence accompanies stem cell ageing in vivo, and in line with p16(INK4A) being a critical determinant of such processes, most aged HSCs (>99%) failed to express p16(INK4A) at the mRNA level. Moreover, whereas loss of epigenetically guided repression of the INK4A/ARF locus accompanied replicative senescent murine embryonic fibroblasts, such repression was maintained in aged stem cells. Taken together, these studies indicate that increased senescence as mediated by the p16(INK4A) tumor suppressor has only a minor function as an intrinsic regulator of steady-state HSC ageing in vivo. Oncogene (2009) 28, 2238-2243; doi: 10.1038/onc.2009.94; published online 27 April 2009