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| Aging: Notching up stem cell differentiation
A mutant form of lamin A activates the Notch signaling pathway to promote precocious mesenchymal stem cell differentiation. Lamin proteins line the interior of the nucleus and contribute to both chromatin structure and gene regulation. A mutant version of lamin A called progerin is known to cause the premature-aging disease Hutchinson–Gilford Progeria Syndrome (HGPS). Constitutive expression of progerin produces nuclear defects and increases DNA damage, although the mechanism of action behind the associated accelerated aging has remained unclear. In Nature Cell Biology, Scaffidi and Misteli now show that progerin promotes premature differentiation of mesenchymal stem cells by upregulating the Notch signaling pathway.
Genome-wide microarray analysis revealed that progerin expression correlated with the induction of Notch pathway proteins in immortalized skin fibroblasts. Whereas cell lines derived from HGPS patients express high levels of progerin and Notch effectors, the amount of Notch intracellular domain (NICD) protein — the active version of Notch that functions as a transcriptional co-activator — remained constant in HGPS cells. This indicates that proteins downstream of NICD may mediate the effect of progerin. Indeed, the Notch target genes' co-activator SKIP (Ski-interacting protein) was upregulated in HGPS cells. Interestingly, SKIP was no longer associated with the nuclear lamina in HGPS cells, suggesting that progerin interferes with normal SKIP localization and permits unregulated SKIP signaling. Bone and adipose tissue originate from mesenchymal progenitor cells and exhibit striking alterations in HGPS patients. Expression of progerin in immortalized human mesenchymal stem cells (hMSCs) not only upregulated Notch pathway effectors, it also caused the misregulation of differentiation markers such as collagen IV and osteopontin in undifferentiated cells. In addition, when lineage-specific differentiation was induced, progerin expression enhanced osteogenesis, but inhibited differentiation of hMSCs into adipose tissue — a hallmark of HGPS. Overexpression of wild-type lamin A protein, however, caused an intermediate phenotype. Expression of NICD in hMSCs similarly induced osteogenic differentiation and blocked adipogenesis, suggesting that the Notch pathway may be involved in HGPS. Indeed, pharmacologic inhibition of Notch signaling partially suppressed the effect of progerin expression in hMSCs. This study shows that progerin activates the Notch pathway, resulting in an abnormal MSC differentiation that may underlie the premature aging of HGPS patients. As normal cells also express low levels of progerin, determining whether progerin plays a role in normal tissue homeostasis to promote terminal differentiation and aging will be important. Emily J. Chenette
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