title: 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 A. Progerin is also expressed sporadically in wild-type cells and has been linked to physiological ageing. Cells from HGPS patients exhibit extensive nuclear defects, including abnormal chromatin structure and increased DNA damage. At the organismal level, HGPS affects several tissues, particularly those of mesenchymal origin. 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.
authors.affiliation: National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. scaffidp@mail.nih.gov
authors.forename: Paola
authors.initials: P
authors.lastname: Scaffidi
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology / Q000502:physiology*; D000375:Aging / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011371:Progeria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; C090764:prelamin A