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

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.

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Figure 1: Activation of Notch signalling pathway effectors in response to progerin.
Figure 2: Activation of Notch signalling pathway effectors in cells from HGPS patients.
Figure 3: Progerin alters the molecular and cellular identity of hMSCs.
Figure 4: Altered differentiation potential of progerin-expressing hMSCs.
Figure 5: Altered differentiation potential of NICD-expressing hMSCs.

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Acknowledgements

We thank A. Magra for help with adipogenesis, J. Roix for help with microarray analysis, T. Voss for help with microscopy, M. Conboy for technical advice on Notch activation, T. Takizawa, R.G. Faragher, T. Glover, J. Toguchida, M. Olive, M. Lazar, T. Ohtsuka, U. Lendahl and A. Marcello for providing reagents. The MPIIIB10 monoclonal antibody developed by M. Solursh was obtained from the Developmental Studies Hybridoma Bank, NICHD, University of Iowa. Fluorescence imaging was performed at the NCI Fluorescence Imaging Facility. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Progeria Research Foundation.

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P.S. and T.M. designed the study and wrote the manuscript. P.S. performed the experiments.

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Correspondence to Paola Scaffidi.

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Supplementary figures S1, S2, S3, S4, S5, S6 and S7 (PDF 1206 kb)

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Scaffidi, P., Misteli, T. Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nat Cell Biol 10, 452–459 (2008). https://doi.org/10.1038/ncb1708

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