Dedifferentiation rescues senescence of progeria cells but only while pluripotent

Hutchinson-Gilford progeria syndrome (HGPS) is an autosomal dominant disease characterized by early onset of several pathologies associated with old age, including arteriosclerosis, strokes, loss of subcutaneous fat, and alopecia. However, patients with HGPS do not develop other pathologies associated with aging (such as neuro-degeneration), suggesting that the pathophysiology is limited to certain cell lineages, particularly those of mesenchymal origin [1]. The disease is caused by a mutation in the LMNA gene encoding the intermediate filament protein lamin A/C, which is critical for nuclear architecture of differentiated cells. The lamins also are important for genome organization, tethering chromatin to the nuclear envelope to help dictate domains of heterochromatin. The HGPS mutation activates a cryptic splice donor site, resulting in synthesis of a dominant negative, incompletely processed form of lamin A, termed progerin [2]. The expression of progerin alters nuclear structure and heterochromatin, affecting cell cycle progression, gene expression, and genomic stability. Progerin is hypothesized to promote sequestration of DNA repair and replication proteins, resulting in a more frequent stalling of replication forks and thereby replication-dependent double-strand breaks [3]. Progerin is farnesylated on its C-terminus, leading to concentration of the truncated protein at the nuclear periphery and leading to rigidity of the normally dynamic nuclear lamina [4], the structure meshwork lining the nuclear membrane. Currently, inhibitors of farnesylation are the only available strategy for treating HGPS but are incompletely effective because they are nonspecific.Interestingly, the cryptic splice site in LMNA is sporadically used in cells from normal individuals, leading to a low-level expression of progerin [5]. Furthermore, fibroblasts from individuals who are more than 80 years old show nuclear abnormalities and changes in heterochromatin markers typical of cells f