Abstract
Vascular disease is one of the leading causes of death worldwide. Vascular repair, essential for tissue maintenance, is critically reduced during vascular disease and aging. Efficient vascular repair requires functional adult stem cells unimpaired by aging or mutation. One protein candidate for reducing stem cell?mediated vascular repair is progerin, an alternative splice variant of lamin A. Progerin results from erroneous activation of cryptic splice sites within the LMNA gene, and significantly increases during aging. Mutations triggering progerin overexpression cause the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), in which patients die at approximately 13-years of age due to atherosclerosis-induced disease. Progerin expression affects tissues rich in cells that can be derived from marrow stromal cells (MSCs. Studies using various MSC subpopulations and models have led to discrepant results. Using a well-defined, immature subpopulation of MSCs, Marrow Isolated Adult Multilineage Inducible (MIAMI) cells, we find progerin significantly disrupts expression and localization of self-renewal markers, proliferation, migration, and membrane elasticity. One potential treatment, farnesyltransferase inhibitor, ameliorates some of these effects. Our results confirm proposed progerin-induced mechanisms and suggest novel ways in which progerin disturbs critical stem cell functions collectively required for proper tissue repair, offering promising treatment targets for future therapies.
Highlights
Mutations in the gene encoding lamin A lead to numerous disorders, collectively known as laminopathies
Many tissues are significantly affected by progerin expression, we focus here on stem cell functions that are relevant for vascular repair
We evaluate progerin effects on stem cell functions critical to vascular repair using a novel model of a homogenous sub-population of developmentally immature marrow stromal cells (MSCs) known as marrowisolated adult multilineage inducible (MIAMI) stem cells
Summary
Mutations in the gene encoding lamin A lead to numerous disorders, collectively known as laminopathies. Lamin A is localized to the nuclear lamina at the inner-side of the nuclear envelope, contributing to nuclear structural stability and other nuclear functions. Lamin A regulates gene expression by directly binding to DNA, and sequesters heterochromatin and silenced or transcriptionally low genes to the periphery of the nucleus. Some other nuclear functions that are regulated by lamin A include DNA replication, DNA repair, chromatin and nuclear pore complex organization, and gene expression [1,2,3]. Lamin A is post-translationally farnesylated, yielding immature, pre-lamin A [1, 3,4,5]. Farnesylation facilitates pre-lamin A integration into the nuclear lamina by virtue of the hydrophobic isoprenoid modification. The farnesylated Cterminus is cleaved by the zinc metalloprotease www.impactaging.com
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