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Thymocytes generated in the bone marrow migrate to the thymus, near the heart, where they mature into T cells of the adaptive immune system. Unfortunately, the thymus atrophies with age. Most people have little active thymus tissue left by the time they are in their 50s. Absent a robust supply of new T cells, the adaptive immune system becomes ever more made up of malfunctioning, senescent, and other problematic cells, lacking the naive T cells needed to respond to new threats. Regeneration of the thymus is thus an important goal. There are some indications that the thymus is more plastic than thought, given that mild calorie restriction in humans produced some gains. Additionally, a growth hormone based therapy has shown some signs of improvement in small human trials. Here, researchers show that stem cell transplantation can produce thymic regrowth in old non-human primates, making this an option that should be evaluated in human patients.
A decrease in the number and activity of thymic epithelial cells (TECs) is an important factor in thymic degeneration. Mesenchymal stem cells (MSCs) treating thymic ageing is a promising strategy. Aged rhesus monkeys were treated with MSCs to establish a thymic senescence model, and hematoxylin-eosin (HE) staining, immunofluorescence staining, and ELISA were performed to observe the structure and function of the thymus. TEC aging model and MSCs co-culture system were established to detect DNA methylation modification and transcriptomic changes, correlation analysis between transcription factor methylation and mRNA expression, and q-PCR, immunofluorescence staining, and Western blot were used to identified key genes.
MSCs improved the structure and function of the thymus in elderly macaque monkeys; reduced the expression levels of β-Gal, P16, and P21; and increased the activity of aging TECs. There were 501 genes with increased methylation in the promoter region in the treated group compared with the untreated group, among which 23 genes were involved in the negative regulation of cell growth, proliferation, and apoptosis, while 591 genes had decreased methylation, among which 37 genes were associated with promoting cell growth and proliferation and inhibiting apoptosis. Furthermore, 66 genes showed a negative correlation between promoter methylation levels and gene transcription; specifically, PDE5A, DUOX2, LAMP1, and SVIL were downregulated with increased methylation, inhibiting growth and development, while POLR3G, PGF, CHTF18, KRT17, FOXJ1, NGF, DYRK3, LRP8, CDT1, PRELID1, F2R, KNTC1, and TRIM3 were upregulated with decreased methylation, promoting cell growth.
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