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.
authors.affiliation: Research Service and Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veteran Affairs Medical Center, Miami, FL 33125, USA. Department of Biochemistry and Molecular Biology University of Miami Miller School of Medicine; Miami, FL 33136, USA.
authors.forename: Laurin Marie
authors.initials: LM
authors.lastname: Pacheco
authors.affiliation: Research Service and Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veteran Affairs Medical Center, Miami, FL 33125, USA.
authors.forename: Lourdes Adriana
authors.initials: LA
authors.lastname: Gomez
authors.affiliation: Department of Biomedical Engineering, University of Miami College or Engineering, Coral Gables, FL 33146, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Dias
authors.affiliation: Department of Biomedical Engineering, University of Miami College or Engineering, Coral Gables, FL 33146, USA.
authors.forename: Noel M
authors.initials: NM
authors.lastname: Ziebarth
authors.affiliation: Research Service and Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veteran Affairs Medical Center, Miami, FL 33125, USA. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Department of Medicine; University of Miami Miller School of Medicine; Miami, FL 33136, USA.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Howard
authors.affiliation: Research Service and Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veteran Affairs Medical Center, Miami, FL 33125, USA. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Department of Orthopaedics; University of Miami Miller School of Medicine; Miami, FL 33136, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Schiller
mesh_terms: D000293:Adolescent; D000328:Adult; D053687:Adult Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002648:Child; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D034904:Lamin Type A; D008297:Male; D008560:Membrane Fluidity; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; C090764:prelamin A; D051231:Farnesyltranstransferase