Wnt4 signaling is associated with the decrease of proliferation and increase of apoptosis during age-related thymic involution

Abstract

The thymus is a central lymphoid organ that is responsible for T-lymphocyte development and maturation. Through negative and positive selection, lymphoid progenitor cells, which initiate from the bone marrow, develop into mature T cells in the thymus, and are subsequently involved in peripheral cell immunity. It has been reported that the Wnt signaling pathway exists widely in thymic epithelial cells and T lymphocytes. Wnt signaling affects the shape and function of thymic epithelial cells and has an important role in maintaining pro-T-cells, and in the subsequent T-cell differentiation. Previous studies have demonstrated that the Wnt signaling pathway participates in age-associated thymic involution. In the present study alterations in proliferation and apoptosis were investigated in murine thymic cells during aging. The results of the present study demonstrated that the aged thymus was characterized by markedly decreased cell numbers, as well as decreased proliferation and increased apoptosis. Concurrently, age-associated changes in thymic cell number and function were accompanied by a decrease in the transcription levels of Wnt4, and downregulation of forkhead box N1 and B-cell lymphoma-extra large, which are two target genes of the Wnt4 signaling pathway. In vitro studies demonstrated that activation of the Wnt4 signaling pathway promotes mouse thymus epithelial cell 1 (MTEC1) cell proliferation, and that Wnt4 signaling modulation alleviates dexamethasone-mediated MTEC1 cell apoptosis. These results suggest that normal expression levels of Wnt4 have a critical role in maintaining the balance between cell proliferation and apoptosis. Alterations in the Wnt signaling pathway may disrupt the epithelial network structure of the thymus, eventually leading to microenvironmental damage. Therefore, further studies regarding the effects of the Wnt signaling pathway on thymus development and age-related thymic involution, may be beneficial for improving the health conditions of the elderly.