Statin treatment of adult human glial progenitors induces PPARγ-mediated oligodendrocytic differentiation

Fraser J. Sim, Jennifer K. Lang, Tracy A. Ali, Neeta Roy, G. Edward Vates, Webster H. Pilcher, Steven A. Goldman

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells. To assess the functional importance of the sterol synthesis pathway to adult human glial progenitors, we used simvastatin or pravastatin to inhibit HMG-CoA reductase, and then assessed the phenotypic differentiation of the progenitors, as well as the molecular concomitants thereof. We found that both statins induced a dose-dependent induction of oligodendrocyte phenotype, and concomitant reduction in progenitor number. Oligodendrocyte commitment was associated with induction of the sterol-regulated nuclear co-receptor PPARγ, and could be blocked by the specific PPARγ antagonist GW9662. Thus, statins may promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells; this might reduce the available progenitor pool, and hence degrade the long-term regenerative competence of the adult white matter.

Original languageEnglish (US)
Pages (from-to)954-962
Number of pages9
JournalGLIA
Volume56
Issue number9
DOIs
StatePublished - Jul 1 2008
Externally publishedYes

Fingerprint

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Peroxisome Proliferator-Activated Receptors
Neuroglia
Oligodendroglia
Sterols
Hydroxymethylglutaryl CoA Reductases
Stem Cells
Therapeutics
Pravastatin
Simvastatin
Cytoplasmic and Nuclear Receptors
Mental Competency
Multiple Sclerosis
Phenotype

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Sim, F. J., Lang, J. K., Ali, T. A., Roy, N., Vates, G. E., Pilcher, W. H., & Goldman, S. A. (2008). Statin treatment of adult human glial progenitors induces PPARγ-mediated oligodendrocytic differentiation. GLIA, 56(9), 954-962. https://doi.org/10.1002/glia.20669

Statin treatment of adult human glial progenitors induces PPARγ-mediated oligodendrocytic differentiation. / Sim, Fraser J.; Lang, Jennifer K.; Ali, Tracy A.; Roy, Neeta; Vates, G. Edward; Pilcher, Webster H.; Goldman, Steven A.

In: GLIA, Vol. 56, No. 9, 01.07.2008, p. 954-962.

Research output: Contribution to journalArticle

Sim, FJ, Lang, JK, Ali, TA, Roy, N, Vates, GE, Pilcher, WH & Goldman, SA 2008, 'Statin treatment of adult human glial progenitors induces PPARγ-mediated oligodendrocytic differentiation', GLIA, vol. 56, no. 9, pp. 954-962. https://doi.org/10.1002/glia.20669
Sim, Fraser J. ; Lang, Jennifer K. ; Ali, Tracy A. ; Roy, Neeta ; Vates, G. Edward ; Pilcher, Webster H. ; Goldman, Steven A. / Statin treatment of adult human glial progenitors induces PPARγ-mediated oligodendrocytic differentiation. In: GLIA. 2008 ; Vol. 56, No. 9. pp. 954-962.
@article{80c24ecabefa446eb4e6dbb9e36a9c2f,
title = "Statin treatment of adult human glial progenitors induces PPARγ-mediated oligodendrocytic differentiation",
abstract = "The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells. To assess the functional importance of the sterol synthesis pathway to adult human glial progenitors, we used simvastatin or pravastatin to inhibit HMG-CoA reductase, and then assessed the phenotypic differentiation of the progenitors, as well as the molecular concomitants thereof. We found that both statins induced a dose-dependent induction of oligodendrocyte phenotype, and concomitant reduction in progenitor number. Oligodendrocyte commitment was associated with induction of the sterol-regulated nuclear co-receptor PPARγ, and could be blocked by the specific PPARγ antagonist GW9662. Thus, statins may promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells; this might reduce the available progenitor pool, and hence degrade the long-term regenerative competence of the adult white matter.",
author = "Sim, {Fraser J.} and Lang, {Jennifer K.} and Ali, {Tracy A.} and Neeta Roy and Vates, {G. Edward} and Pilcher, {Webster H.} and Goldman, {Steven A.}",
year = "2008",
month = "7",
day = "1",
doi = "10.1002/glia.20669",
language = "English (US)",
volume = "56",
pages = "954--962",
journal = "GLIA",
issn = "0894-1491",
publisher = "John Wiley and Sons Inc.",
number = "9",

}

TY - JOUR

T1 - Statin treatment of adult human glial progenitors induces PPARγ-mediated oligodendrocytic differentiation

AU - Sim, Fraser J.

AU - Lang, Jennifer K.

AU - Ali, Tracy A.

AU - Roy, Neeta

AU - Vates, G. Edward

AU - Pilcher, Webster H.

AU - Goldman, Steven A.

PY - 2008/7/1

Y1 - 2008/7/1

N2 - The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells. To assess the functional importance of the sterol synthesis pathway to adult human glial progenitors, we used simvastatin or pravastatin to inhibit HMG-CoA reductase, and then assessed the phenotypic differentiation of the progenitors, as well as the molecular concomitants thereof. We found that both statins induced a dose-dependent induction of oligodendrocyte phenotype, and concomitant reduction in progenitor number. Oligodendrocyte commitment was associated with induction of the sterol-regulated nuclear co-receptor PPARγ, and could be blocked by the specific PPARγ antagonist GW9662. Thus, statins may promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells; this might reduce the available progenitor pool, and hence degrade the long-term regenerative competence of the adult white matter.

AB - The statins have been proposed as possible therapeutic agents for a variety of autoimmune disorders, including multiple sclerosis. In a genomic screen, we found that glial progenitor cells (GPCs) of the adult human white matter expressed significant levels of the principal statin target, HMG-CoA reductase, as well as additional downstream members of the sterol synthesis pathway. We therefore asked if statin treatment might influence the differentiated fate of adult glial progenitor cells. To assess the functional importance of the sterol synthesis pathway to adult human glial progenitors, we used simvastatin or pravastatin to inhibit HMG-CoA reductase, and then assessed the phenotypic differentiation of the progenitors, as well as the molecular concomitants thereof. We found that both statins induced a dose-dependent induction of oligodendrocyte phenotype, and concomitant reduction in progenitor number. Oligodendrocyte commitment was associated with induction of the sterol-regulated nuclear co-receptor PPARγ, and could be blocked by the specific PPARγ antagonist GW9662. Thus, statins may promote oligodendrocyte lineage commitment by parenchymal glial progenitor cells; this might reduce the available progenitor pool, and hence degrade the long-term regenerative competence of the adult white matter.

UR - http://www.scopus.com/inward/record.url?scp=51349103902&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=51349103902&partnerID=8YFLogxK

U2 - 10.1002/glia.20669

DO - 10.1002/glia.20669

M3 - Article

C2 - 18383345

AN - SCOPUS:51349103902

VL - 56

SP - 954

EP - 962

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 9

ER -