Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing

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Abstract
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 A1,2. Progerin is also expressed sporadically in wild-type cells and has been linked to physiological ageing3. Cells from HGPS patients exhibit extensive nuclear defects, including abnormal chromatin structure4,5 and increased DNA damage6. At the organismal level, HGPS affects several tissues, particularly those of mesenchymal origin7. 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.