title: A human iPSC model of Hutchinson Gilford Progeria reveals vascular smooth muscle and mesenchymal stem cell defects.
abstract: The segmental premature aging disease Hutchinson-Gilford Progeria syndrome (HGPS) is caused by a truncated and farnesylated form of Lamin A called progerin. HGPS affects mesenchymal lineages, including the skeletal system, dermis, and vascular smooth muscle (VSMC). To understand the underlying molecular pathology of HGPS, we derived induced pluripotent stem cells (iPSCs) from HGPS dermal fibroblasts. The iPSCs were differentiated into neural progenitors, endothelial cells, fibroblasts, VSMCs, and mesenchymal stem cells (MSCs). Progerin levels were highest in MSCs, VSMCs, and fibroblasts, in that order, with these lineages displaying increased DNA damage, nuclear abnormalities, and HGPS-VSMC accumulating numerous calponin-staining inclusion bodies. Both HGPS-MSC and -VSMC viability was compromised by stress and hypoxia in vitro and in vivo (MSC). Because MSCs reside in low oxygen niches in vivo, we propose that, in HGPS, this causes additional depletion of the MSC pool responsible for replacing differentiated cells lost to progerin toxicity.
authors.affiliation: Stem Cell Disease Models, A*STAR Institute of Medical Biology, Singapore 138648, Singapore.
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Zhang
authors.forename: Qizhou
authors.initials: Q
authors.lastname: Lian
authors.forename: Guili
authors.initials: G
authors.lastname: Zhu
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.forename: Lin
authors.initials: L
authors.lastname: Sui
authors.forename: Cindy
authors.initials: C
authors.lastname: Tan
authors.forename: Rafidah Abdul
authors.initials: RA
authors.lastname: Mutalif
authors.forename: Raju
authors.initials: R
authors.lastname: Navasankari
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Alan
authors.initials: A
authors.lastname: Colman
mesh_terms: D019588:Aging, Premature / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000473:pathology*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism; D011371:Progeria / Q000473:pathology / Q000628:therapy
chemical_list: D010100:Oxygen