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

Laurin Marie Pacheco, Lourdes Adriana Gomez, Janice Dias, Noel Marysa Ziebarth, Guy Howard, Paul C Schiller

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1049-1063
Number of pages15
JournalAging
Volume6
Issue number12
StatePublished - Jan 1 2014

Fingerprint

Adult Stem Cells
Stromal Cells
Bone Marrow
Blood Vessels
Vascular Diseases
Stem Cells
Progeria
Lamin Type A
Farnesyltranstransferase
Premature Aging
RNA Splice Sites
Mutation
Cell Aging
Elasticity
Cause of Death
Atherosclerosis
Therapeutics
Maintenance
Membranes
Genes

Keywords

  • aging
  • HGPS
  • Hutchinson-gilford progeria syndrome
  • MSC
  • Progeria
  • progerin

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Progerin expression disrupts critical adult stem cell functions involved in tissue repair. / Pacheco, Laurin Marie; Gomez, Lourdes Adriana; Dias, Janice; Ziebarth, Noel Marysa; Howard, Guy; Schiller, Paul C.

In: Aging, Vol. 6, No. 12, 01.01.2014, p. 1049-1063.

Research output: Contribution to journalArticle

Pacheco, Laurin Marie ; Gomez, Lourdes Adriana ; Dias, Janice ; Ziebarth, Noel Marysa ; Howard, Guy ; Schiller, Paul C. / Progerin expression disrupts critical adult stem cell functions involved in tissue repair. In: Aging. 2014 ; Vol. 6, No. 12. pp. 1049-1063.
@article{4399ff306c5b43a29e11578a31990fc1,
title = "Progerin expression disrupts critical adult stem cell functions involved in tissue repair",
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.",
keywords = "aging, HGPS, Hutchinson-gilford progeria syndrome, MSC, Progeria, progerin",
author = "Pacheco, {Laurin Marie} and Gomez, {Lourdes Adriana} and Janice Dias and Ziebarth, {Noel Marysa} and Guy Howard and Schiller, {Paul C}",
year = "2014",
month = "1",
day = "1",
language = "English",
volume = "6",
pages = "1049--1063",
journal = "Aging",
issn = "1945-4589",
publisher = "US Administration on Aging",
number = "12",

}

TY - JOUR

T1 - Progerin expression disrupts critical adult stem cell functions involved in tissue repair

AU - Pacheco, Laurin Marie

AU - Gomez, Lourdes Adriana

AU - Dias, Janice

AU - Ziebarth, Noel Marysa

AU - Howard, Guy

AU - Schiller, Paul C

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - aging

KW - HGPS

KW - Hutchinson-gilford progeria syndrome

KW - MSC

KW - Progeria

KW - progerin

UR - http://www.scopus.com/inward/record.url?scp=84920929019&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920929019&partnerID=8YFLogxK

M3 - Article

VL - 6

SP - 1049

EP - 1063

JO - Aging

JF - Aging

SN - 1945-4589

IS - 12

ER -