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.

Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells

“…Indeed, the hiPS cell-derived vascular precursor cells have been shown to be excellent models to study disease. For example, hiPS cell-derived vascular precursors have been used to derive blood-brain barrier type endothelial cells (ECs) in culture (14) or to study patientspecific EC and smooth muscle cell defects in a Hutchinson Gilford progeria model (15) and rescue the vascular phenotype of Williams-Beuren syndrome (16).…”

Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

“…Furthermore, even though the miR-9-binding site in the prelamin A 3′ UTR is conserved in humans, we do not know if its functional significance is conserved also. In any case, we were intrigued by recent studies of lamin A/C expression in induced pluripotent stem cells generated from human HGPS fibroblasts (27). Upon differentiation into mesenchymal stem cells, lamin A and progerin were expressed highly, but when the same cells were differentiated into neural progenitors, lamin C was the predominant isoform, and the levels of lamin A and progerin were low (27).…”

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

“…of examples illustrate how such cells, retrieved from genetically selected donors carrying the causal mutation of a monogenic disorder, may reproduce disease-associated phenotypes (22)(23)(24)(25)(26). Thus, we used two human embryonic stem cell (hESC) lines derived from embryos characterized as mutant gene carriers for NF1 during a preimplantation diagnosis procedure, to explore mechanisms associated with hyperpigmentation in melanocytes and potential treatments for the pathological phenotype.…”