wnt4 and lap2alpha as pacemakers of thymic epithelial senescencewnt4和lap2alpha胸腺上皮细胞衰老的心脏起搏器.pdf

Wnt4 and LAP2alpha as Pacemakers of Thymic Epithelial Senescence 1 1 1 1 2 Krisztian Kvell , Zoltan Varecza , Domokos Bartis , Sebastian Hesse , Sonia Parnell , Graham 2 2 1,2 Anderson , Eric J. Jenkinson , Judit E. Pongracz * 1 Department of Medical Biotechnology, Institute for Immunology and Biotechnology, University of Pecs, Pecs, Hungary, 2 Division of Immunity and Infection, Department of Anatomy, Institute for Biomedical Research, University of Birmingham, Birmingham, United Kingdom 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 LAP2a 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 LAP2a and Wnt4-over-expressing thymic