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Research Paper|Volume 6, Issue 12|pp 1049—1063

Progerin expression disrupts critical adult stem cell functions involved in tissue repair

Laurin Marie Pacheco1,2, Lourdes Adriana Gomez1, Janice Dias3, Noel M Ziebarth3, Guy A Howard1,2,4, Paul C Schiller1,2,5
  • 1Research Service and Geriatric Research, Education, and Clinical Center; Bruce W. Carter Veteran Affairs Medical Center; Miami, FL 33125, USA
  • 2Department of Biochemistry and Molecular Biology; University of Miami Miller School of Medicine; Miami, FL 33136, USA
  • 3Department of Biomedical Engineering; University of Miami College of Engineering; Coral Gables, FL 33146, USA
  • 4Department of Medicine; University of Miami Miller School of Medicine; Miami, FL 33136, USA
  • 5Department of Orthopaedics; University of Miami Miller School of Medicine; Miami, FL 33136, USA
Received: September 10, 2014Accepted: December 20, 2014Published: December 21, 2014
https://doi.org/10.18632/aging.100709

Copyright: © 2014 Pacheco et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.