Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
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DOI：
10.1038/nature05159
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发表时间：
2006-09-28
期刊：
影响因子：
64.8
通讯作者：
Scadden, David T.
中科院分区：
文献类型：
--
作者：
Janzen, Viktor;Forkert, Randolf;Scadden, David T.
干细胞老化被认为有助于改变组织的维持和修复。老年人经历骨髓衰竭增加和细胞毒性损伤的血液学耐受性较差。老年小鼠的造血干细胞（HSC）具有降低的每细胞再生活性、自我更新和归巢能力、髓样分化偏斜以及应激引起的凋亡增加。在这里，我们报告的细胞周期蛋白依赖性激酶抑制剂p16（INK4a），其水平先前指出，增加在其他类型的细胞随着年龄的增长，积累和调制特定的年龄相关的HSC功能。值得注意的是，在p16（INK4a）不存在的情况下，HSC再增殖缺陷和细胞凋亡被减轻，改善了细胞的应激耐受性和动物在连续移植（干细胞自主组织再生模型）中的存活。抑制p16（INK4a）可以改善衰老对干细胞的生理影响，从而改善衰老组织的损伤修复。
Stem-cell ageing is thought to contribute to altered tissue maintenance and repair. Older humans experience increased bone marrow failure and poorer haematologic tolerance of cytotoxic injury. Haematopoietic stem cells (HSCs) in older mice have decreased per-cell repopulating activity, self-renewal and homing abilities, myeloid skewing of differentiation, and increased apoptosis with stress. Here we report that the cyclin-dependent kinase inhibitor p16(INK4a), the level of which was previously noted to increase in other cell types with age, accumulates and modulates specific age-associated HSC functions. Notably, in the absence of p16(INK4a), HSC repopulating defects and apoptosis were mitigated, improving the stress tolerance of cells and the survival of animals in successive transplants, a stem- cell-autonomous tissue regeneration model. Inhibition of p16(INK4a) may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue.