Researchers here report on a cell based approach to regeneration of the aged thymus. The thymus is responsible for maturation of T cells of the adaptive immune system. Unfortunately, this organ atrophies with age for reasons that appear connected to chronic inflammation, but are far from fully explored. This loss of active thymic tissue greatly reduces the pace at which the adaptive immune system is supplied with replacement cells, and is a major contributing factor to the loss of immune function that emerges with advancing age.

Regeneration of the thymus is thus an important project for human rejuvenation, and numerous approaches to this goal are at various, largely early stages of development. Like most demonstrations in mice carried out to date, the cell therapy in this case involves direct introduction of material into the thymus. This requirement makes a strategy more challenging to use as a basis for therapies intended to prevent immune aging. The thymus is very inconveniently located, under the sternum and over the heart, and any sort of direct injection into the depths of the chest is likely to have too high a rate of complication and mortality in older people for regulators to allow it to be applied preventatively to a large fraction of the population.

Age-associated systemic, chronic inflammation is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. This involution causally results from gradually decreased expression of the transcription factor FOXN1 in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can partially rescue age-related thymic involution. Given the findings that TECs induced from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected naturally young TECs can lead to middle-aged thymus regrowth, we attempted to extend these two findings by combining them as a novel thymic rejuvenation strategy with two types of promoter-driven FOXN1-reprogrammed embryonic fibroblasts (FREFs).

We engrafted these two-types of FREFs directly into the aged murine thymus. We found significant regrowth of the native aged thymus with rejuvenated architecture and function in both males and females, exhibiting increased thymopoiesis and reinforced thymocyte negative selection, along with reduced senescent T cells and auto-reactive T cell-mediated inflammation in old mice. Therefore, this strategy has preclinical significance and presents a strategy to potentially rescue decreased thymopoiesis and perturbed negative selection to significantly, albeit partially, restore defective central tolerance and reduce subclinical autoimmune symptoms in the elderly.