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.
Highlights
Thymic senescence Thymic senescence begins early, around late puberty
The simultaneous increase in LAP2a expression provides the necessary signal that pushes dedifferentiated thymic epithelial cells to differentiate into preadipocytes, as detected by increased mRNA levels of PPARc and ADRP
The first allows for the direct initiation of pre-adipocyte differentiation from de-differentiated thymic epithelial cells due to the down-regulation of Wnt4 and up-regulation of LAP2a
Summary
Thymic senescence Thymic senescence begins early, around late puberty. This process is called adipose involution, as the thymus is invaded by adipose tissue [1]. Due to decrease in thymic epithelial tissue mass, the thymus can no longer support the same output of T-cell production [2]. Peripheral blood T lymphocyte composition exhibits the dominance of memory T lymphocytes resulting in impaired responses towards novel, viral infections [3,4,5]. Since the thymic epithelium has a key role in deleting auto-reactive T-cell clones, functional impairment increases the chances of developing auto-immune disease [6]. If we were able to slow down or even stop the loss of thymic epithelium the elderly would have a better chance to address lateonset autoimmune diseases and viral infections. Despite studies of thymic senescence, the molecular mechanism of thymic aging remains elusive
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