Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing
Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing
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DOI：
10.1038/ncb1708
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发表时间：
2008-04-01
影响因子：
21.3
通讯作者：
Misteli, Tom
中科院分区：
文献类型：
--
作者：
Scaffidi, Paola;Misteli, Tom
早老性疾病Hutchinson-Gilford早衰综合征（HGPS）是由组成性生产早衰蛋白引起的，早衰蛋白是核结构蛋白层蛋白a的一种突变形式（1,2）。Progerin也在野生型细胞中零星表达，并与生理衰老有关(3)。HGPS患者的细胞表现出广泛的核缺陷，包括染色质结构异常（4,5）和DNA损伤增加(6)。在机体水平上，HGPS影响多种组织，尤其是间充质起源的组织(7)。HGPS细胞的细胞缺陷是如何导致机体缺陷的尚不清楚。在这里，我们提供的证据表明，progerin干扰人间充质干细胞（hMSCs）的功能。我们发现progerin的表达激活了Notch信号通路的主要下游效应物。在hMSCs中诱导progerin改变其分子特性和分化潜能。我们的研究结果支持一个模型，即HGPS患者的加速衰老，可能也是生理性衰老，是成体干细胞功能障碍和组织功能进行性恶化的结果。
The premature-ageing disease Hutchinson-Gilford Progeria Syndrome ( HGPS) is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A(1,2). Progerin is also expressed sporadically in wildtype cells and has been linked to physiological ageing(3). Cells from HGPS patients exhibit extensive nuclear defects, including abnormal chromatin structure(4,5) and increased DNA damage(6). At the organismal level, HGPS affects several tissues, particularly those of mesenchymal origin(7). How the cellular defects of HGPS cells lead to the organismal defects has been unclear. Here, we provide evidence that progerin interferes with the function of human mesenchymal stem cells ( hMSCs). We find that expression of progerin activates major downstream effectors of the Notch signalling pathway. Induction of progerin in hMSCs changes their molecular identity and differentiation potential. Our results support a model in which accelerated ageing in HGPS patients, and possibly also physiological ageing, is the result of adult stem cell dysfunction and progressive deterioration of tissue functions.