Recapitulation of premature ageing with iPSCs from Hutchinson–Gilford progeria syndrome

Guang-Hui Liu ,. et al. 2011. Nature 472, 221–225

Speaker: Zhou Yu (周 妤)                                     Time: 13:00~14:00, April 27, 2011

Commentator: Dr. Yuan Guo (袁 國博士)          Place: Room 601

Abstract:

Hutchinson–Gilford progeria syndrome (HGPS) is a genetic condition characterized by the dramatic rapid appearance of aging beginning in childhood. Affected children typically look normal at birth and in early infancy, but then grow more slowly than other children and do not gain weight at the expected rate (failure to thrive). Unfortunately, progeria often leads to death caused by atherosclerosis at an average age of thirteen years .HGPS is caused by an accumulation of progerin, a truncated splicing mutant of lamin A. which affects mesenchymal lineages, including the skeletal system, dermis, and vascular smooth muscle (VSMC). To understand the underlying molecular pathology of HGPS, the authors generated induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS by transducing retroviruses encoding OCT4, SOX2, KLF4, c-MYC and green florescent protein (GFP), which are important for maintaining the defining properties of embryonic stem cells. The iPSCs were differentiated into fibroblasts and mesenchymal stem cells (MSCs). HGPS-iPSCs complete loss the expression of progerin, reset the nuclear defect and epigenetic alterations associated with premature ageing. The cells differentiation from HGPS-iPSs which were truncated letivirus vector expressing a progerin-specific short hairpin RNA (shRNA) show downregulated level of progerin and improved proliferation capability compared to control cell. Furthermore, they identified DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a downstream target of progerin by immunoprecipitated (IP), the data indicated that downregulation of DNAPKcs in HGPS cells is dependent on the accumulation of progerin in differentiated cells and they found when knockdown of DNAPKcs the proliferation of primary vascular SMCs was reduce. Altogether, the altered structure of the nuclear envelope, as well as the epigenetic modifications accumulate during physiological ageing can be restored to normally by reprogrammed. This study may provide a model to study the pathogenesis of human ageing-related vascular diseases and various human laminopathies.

References:

1.      Worman, H. J., et al. 2010. Diseases of the nuclear envelope. Cold Spring Harb. Perspect. Biol. 2, a000760.

2.      Zhang, J., et al. 2011. A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects. Cell Stem Cell. 8, 31–45