WNT signaling suppression in the senescent human thymus

Abstract

Human thymus is completely developed in late fetal stages and its function peaks in newborns. After the first year of life, the thymus undergoes a progressive atrophy that dramatically decreases de novo T-lymphocyte maturation. Hormonal signaling and changes in the microRNA expression network are identified as underlying causes of human thymus involution. However, specific pathways involved in the age-related loss of thymic function remain unknown. In this study, we analyzed differential gene-expression profile and microRNA expression in elderly (70 years old) and young (less than 10 months old and 11 years old) human thymic samples. Our data have shown that WNT pathway deregulation through the overexpression of different inhibitors by the nonadipocytic component of the human thymus stimulates the age-related involution. These results are of particular interest because interference of WNT signaling has been demonstrated in both animal models and in vitro studies, with the three major hallmarks of thymic involution: (i) epithelial structure disruption, (ii) adipogenic process, and (iii) thymocyte development arrest. Thus, our results suggest that secreted inhibitors of the WNT pathway could be explored as a novel therapeutical target in the reversal of the age-related thymic involution.

Keywords: Aging.; Human thymus; Thymus involution; WNT pathway.

Figure 1.

Fold change versus corrected p value (by a false discovery rate–corrected threshold of 0.05) from all age-related deregulated genes. WNT pathway genes are highlighted with crosses. From them, the sFRP extracellular inhibitors and the TIMP4 cytoplasmatic inhibitor are the most significantly deregulated (upregulated). PPARγ was also strongly upregulated.

Figure 2.

(A) Visual representation (heat map) of WNT-related altered genes. Downregulated = blue. Upregulated = red. (B) Schematic representation of the WNT pathway. The results of the microarray analysis showed the red-marked WNT mediators as upregulated, whereas green-marked WNT mediators were found downregulated, in involuted (elderly) thymus samples. Four thymic tissue samples were analyzed for each group.

Figure 2.

(A) Visual representation (heat map) of WNT-related altered genes. Downregulated = blue. Upregulated = red. (B) Schematic representation of the WNT pathway. The results of the microarray analysis showed the red-marked WNT mediators as upregulated, whereas green-marked WNT mediators were found downregulated, in involuted (elderly) thymus samples. Four thymic tissue samples were analyzed for each group.

Figure 3.

Quantitative polymerase chain reaction validation. Young (11 years old, n = 4)—light gray bars—and old (70 years old, n = 3)—dark gray bars—expression patterns compared with 10-month-old infants in (A) complete human thymic tissue and (B) adipocyte-depleted human thymic tissue. (C) Old (70 years old, n = 3) versus middle-aged (50 years old, n = 3) human thymus–derived adipocytes. (D) Adipocyte-depleted old (70 years old, n = 3) versus adipocyte-depleted middle-aged (50 years old, n = 3) human thymic tissue. In all figures, the log ratio value of ±0.3 (equivalent to a twofold change) cutoff value is showed as a sensitivity limit of differences between groups.