Growing a New Thymus From Engineered Cells
The thymus is vital to generation of new immune cells, and the fact that it atrophies early in life, turning a river of new cells into a trickle, is one of the factors placing an effective cap on the adult immune cell population. In part because of this limit in later life competent immune cells capable of dealing with new threats are crowded out by other immune cell types. Solutions to this issue include restoration of a larger supply of new cells by restoring the thymus or targeted destruction of the excess cells to free up space and spur the body to generate replacement immune cells that are capable of doing their jobs.
Earlier this year researchers published a demonstration of a short cut to rejuvenate the aged thymus simply by manipulating levels of FOXN1 to boost the population of certain important progenitor cells responsible for maintaining the thymus. It is rare to find such short cuts in tissue engineering, and this one most likely only exists for the thymus because of its unusual early decline in adults - a course very different from most organs, and which may have a comparatively simple set of triggers. Here the same research group shows off the next stage in their work, which is the generation of a complete new thymus in vivo by much the same set of mechanisms:
[Scientists] started with cells from a mouse embryo. These cells were genetically "reprogrammed" and started to transform into a type of cell found in the thymus. These were mixed with other support-role cells and placed inside mice. Once inside, the bunch of cells developed into a functional thymus. Structurally it contained the two main regions - the cortex and medulla - and it also produced T-cells. "This was a complete surprise to us, that we were really being able to generate a fully functional and fully organised organ starting with reprogrammed cells in really a very straightforward way. This is a very exciting advance and it's also very tantalising in terms of the wider field of regenerative medicine."Here, we show that enforced Foxn1 expression is sufficient to reprogramme fibroblasts into functional thymic epithelial cells (TECs), an unrelated cell type across a germ-layer boundary. On transplantation, iTECs established a complete, fully organized and functional thymus, that contained all of the TEC subtypes required to support T-cell differentiation and populated the recipient immune system with T cells. iTECs thus demonstrate that cellular reprogramming approaches can be used to generate an entire organ, and open the possibility of widespread use of thymus transplantation to boost immune function in patients.
Patients who need a bone marrow transplant and children who are born without a functioning thymus could all benefit. Ways of boosting the thymus could also help elderly people. The organ shrinks with age and leads to a weaker immune system. However, there are a number of obstacles to overcome before this research moves from animal studies to hospital therapies. The current technique uses embryos. This means the developing thymus would not be a tissue match for the patient. Researchers also need to be sure that the transplant cells do not pose a cancer risk by growing uncontrollably.
With the original research the scientists rejuvinated the thymus using mice genetically engineered to upregulate foxn1 in response to a drug. The big question was how to achieve a similar effect in animals not genetically modified at the germline? Target thymic gene therapy?
This new research suggests that ex vivo transformation of fibroblasts into iTECs which can then just ve injected into the withered thymus (or elsewhere in the body) will do the trick. So the delivery problem has been solved perhaps?