Journal
NATURE CELL BIOLOGY
Volume 10, Issue 4, Pages 452-U167Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1708
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Funding
- Intramural NIH HHS [Z01 BC010309-09] Funding Source: Medline
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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.
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