Wnt4 and LAP2alpha as Pacemakers of Thymic Epithelial Senescence

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Wnt4 and LAP2alpha as Pacemakers of Thymic Epithelial Senescence. / Kvell, K; Varecza, Z; Bartis, D; Hesse, S; Parnell, Sonia; Anderson, Graham; Jenkinson, Eric; Pongracz, JE.

In: PLoS ONE, Vol. 5, No. 5, 01.05.2010, p. e10701.

Research output: Contribution to journalArticlepeer-review

Harvard

Kvell, K, Varecza, Z, Bartis, D, Hesse, S, Parnell, S, Anderson, G, Jenkinson, E & Pongracz, JE 2010, 'Wnt4 and LAP2alpha as Pacemakers of Thymic Epithelial Senescence', PLoS ONE, vol. 5, no. 5, pp. e10701. https://doi.org/10.1371/journal.pone.0010701

APA

Kvell, K., Varecza, Z., Bartis, D., Hesse, S., Parnell, S., Anderson, G., Jenkinson, E., & Pongracz, JE. (2010). Wnt4 and LAP2alpha as Pacemakers of Thymic Epithelial Senescence. PLoS ONE, 5(5), e10701. https://doi.org/10.1371/journal.pone.0010701

Vancouver

Author

Kvell, K ; Varecza, Z ; Bartis, D ; Hesse, S ; Parnell, Sonia ; Anderson, Graham ; Jenkinson, Eric ; Pongracz, JE. / Wnt4 and LAP2alpha as Pacemakers of Thymic Epithelial Senescence. In: PLoS ONE. 2010 ; Vol. 5, No. 5. pp. e10701.

Bibtex

@article{e212b6e16e364cd7bb0b61e891c10314,
title = "Wnt4 and LAP2alpha as Pacemakers of Thymic Epithelial Senescence",
abstract = "Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes.",
author = "K Kvell and Z Varecza and D Bartis and S Hesse and Sonia Parnell and Graham Anderson and Eric Jenkinson and JE Pongracz",
year = "2010",
month = may,
day = "1",
doi = "10.1371/journal.pone.0010701",
language = "English",
volume = "5",
pages = "e10701",
journal = "PLoSONE",
issn = "1932-6203",
publisher = "Public Library of Science (PLOS)",
number = "5",

}

RIS

TY - JOUR

T1 - Wnt4 and LAP2alpha as Pacemakers of Thymic Epithelial Senescence

AU - Kvell, K

AU - Varecza, Z

AU - Bartis, D

AU - Hesse, S

AU - Parnell, Sonia

AU - Anderson, Graham

AU - Jenkinson, Eric

AU - Pongracz, JE

PY - 2010/5/1

Y1 - 2010/5/1

N2 - Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes.

AB - Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes.

U2 - 10.1371/journal.pone.0010701

DO - 10.1371/journal.pone.0010701

M3 - Article

C2 - 20502698

VL - 5

SP - e10701

JO - PLoSONE

JF - PLoSONE

SN - 1932-6203

IS - 5

ER -