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The thymus is where T cells of the adaptive immune system mature: thymocytes are generated in the bone marrow, migrate to the thymus, and become T cells there. Unfortunately, the thymus atrophies with age, and the resultant reduction in the supply of new T cells is most likely an important contributing cause of the age-related decline of the immune system. Over the years, the research community has investigated a broad range of methods by which the thymus might be regrown, most of which focus on providing signal proteins or regulatory proteins in order to spur greater replication and activity of the thymic epithelial cells that carry out the important work of T cell maturation. Researchers here demonstrate a novel approach in this category, using exosomes that home to the thymus and, based on results in cell studies, may then act to spur some degree of regrowth.
Transcription factor FoxN1 is the mastermind of thymus organogenesis and identity, and is also an acknowledged direct molecular target of the glycolipoprotein Wnt4. As a consequence, Wnt4 plays a key role during embryonic thymus development and the maintenance of its identity in adulthood. Thymic epithelial cells secrete less Wnt4, while their Frizzled receptors (Fz4 and Fz6) become up-regulated indicating a potential compensatory mechanism and possibly enhanced Wnt4-binding. This loss of Wnt4 expression weakens thymic epithelial identity and allows for thymic adipose involution to occur. This latter process leads to the expansion of thymic adipose tissue orchestrated by transcription factor PPARgamma. The Wnt/b-catenin pathway and PPARgamma have been reported to act as mutual inhibitors of one another in several tissue contexts, including the thymus. We have previously shown that the addition of exogenous Wnt4 reinforces thymic epithelial identity and confers resistance in a steroid-induced model of senescence through suppressing PPARgamma.
Recent publications of various tissue contexts have suggested that Wnt molecules (including Wnt4) travel in conjunction with extracellular vesicles (EVs), more specifically exosomes. It has also been reported that a significant portion of the Wnts – including Wnt4 – may actually be displayed on exosomal surfaces. EVs are released by most cell types of all phyla and mediate various biological effects. Biological functions attributed with exosomes encompass several physiological and pathological conditions, including cell and tissue regeneration. The thymus epithelium has also been reported to be a rich source of exosomes with key immunological relevance e.g., in thymocyte selection. Yet to date, TEC (thymic epithelial cell) exosomes have not been linked with thymus tissue regeneration.
Our goal was to evaluate the Wnt4 and miR27b levels of Wnt4-transgenic thymic epithelial cell (TEC)-derived exosomes, show their regenerative potential against age-related thymic degeneration, and visualize their binding and distribution both in vitro and in vivo. First, transgenic exosomes were harvested from Wnt4 over-expressing TECs and analyzed by transmission electron microscopy. For functional studies, steroid-induced TECs were used as cellular aging models in which steroid-triggered cellular aging was efficiently prevented by transgenic exosomes. Finally, DiI lipid-stained exosomes were applied on the mouse thymus sections and also iv-injected into mice, for in vitro binding and in vivo tracking, respectively. In vivo injected DiI lipid-stained transgenic exosomes showed detectable homing to the thymus.
In summary, our findings indicate that exosomal Wnt4 and miR27b can efficiently counteract thymic adipose involution. Although extrapolation of mouse results to the human setting needs caution, our results appoint transgenic TEC exosomes as promising tools of immune rejuvenation.