title: Recapitulation of premature ageing with iPSCs from Hutchinson-Gilford progeria syndrome.
abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature ageing disease, characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs). HGPS is caused by a single point mutation in the lamin A (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature ageing. Upon differentiation of HGPS-iPSCs, progerin and its ageing-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular ageing. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs, also known as PRKDC) as a downstream target of progerin. The absence of nuclear DNAPK holoenzyme correlates with premature as well as physiological ageing. Because progerin also accumulates during physiological ageing, our results provide an in vitro iPSC-based model to study the pathogenesis of human premature and physiological vascular ageing.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Liu
authors.forename: Basam Z
authors.initials: BZ
authors.lastname: Barkho
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz
authors.forename: Dinh
authors.initials: D
authors.lastname: Diep
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.forename: Sheng-Lian
authors.initials: SL
authors.lastname: Yang
authors.forename: Athanasia D
authors.initials: AD
authors.lastname: Panopoulos
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Leo
authors.initials: L
authors.lastname: Kurian
authors.forename: Christopher
authors.initials: C
authors.lastname: Walsh
authors.forename: James
authors.initials: J
authors.lastname: Thompson
authors.forename: Stephanie
authors.initials: S
authors.lastname: Boue
authors.forename: Ho Lim
authors.initials: HL
authors.lastname: Fung
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sancho-Martinez
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Yates
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
mesh_terms: D000375:Aging / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D019588:Aging, Premature / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000032:analysis; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D016922:Cellular Senescence; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000473:pathology; D020035:Holoenzymes / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D034904:Lamin Type A; D008840:Microfilament Proteins / Q000032:analysis; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009685:Nuclear Envelope / Q000473:pathology; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011371:Progeria / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D000096985:Calponins
chemical_list: D002135:Calcium-Binding Proteins; D051747:DNA-Activated Protein Kinase; D020035:Holoenzymes; D034904:Lamin Type A; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; D000096985:Calponins; C090764:prelamin A; C497263:PRKDC protein, human