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Their work is an important step towards having the ability to build artificial thymi that could be utilised as transplants.
The thymus is an organ in the chest where T lymphocytes, which play a vital role in the immune system, mature. If the thymus doesn’t work properly or doesn’t form during foetal development in the womb, this may lead to diseases such as severe immunodeficiency, where the body can’t fight infectious diseases or cancerous cells, or autoimmunity, where the immune system mistakenly attacks the patient’s own healthy tissue.
Within their proof-of-concept study, published in Nature Communications today [Friday 11th December], the scientists rebuilt thymi using stem cells taken from patients who had to have the organ removed during operation. When transplanted into mice, the bioengineered thymi were able to support the development of mature and functional human T lymphocytes.
While researchers have rebuilt other organs or segments of organs, this is the first-time scientists have rebuilt an entire working human thymus. The analysis, which was mainly funded by the European Research Council (ERC),* is an important step not only for further research into and treatment of severe immune deficiencies but also more broadly for developing new techniques to grow artificial organs.
Sara Campinoti, author and researcher at the Epithelial Stem Cell Biology and Regenerative Medicine Laboratory at the Crick states:”Showing it is possible to build a working thymus from human cells is a crucial step towards being able to grow thymi which could one day be used as transplants”.
To reconstruct this organ, the researchers gathered thymi from patients and in the lab, grew thymic epithelial cells and thymic interstitial cells from the donated tissue into many colonies of billions of cells.
The next step for the researchers was to get a structural scaffold of thymi, they could repopulate with the thymic cells they had cultured. For this, researcher Asllan Gjinovci developed a fresh approach to remove all of the cells from rat thymi, so only the structural scaffolds remained. They needed to use a new microvascular surgical approach for this, as traditional methods aren’t successful for the thymus.
Asllan says:”This new strategy is important because it enables us to obtain scaffolds from larger organs such as the human thymus, something essential to bringing this beautiful work to the clinic.”
The researchers then injected the organ scaffolds with around six million human thymic epithelial cells in addition to interstitial cells from the colonies that they had grown in the laboratory. The cells climbed onto the scaffolds and after just five days, the organs had grown to a similar stage as those found in nine-week old foetuses.
Finally, the team planted these thymi into mice. They found that in over 75 percent of cases, the thymi were able to support the growth of human lymphocytes.
Roberta Ragazzini, another author of the paper, adds:”The fact that we can extensively expand thymic stem cells taken from human donors into large colonies is actually exciting. It makes it possible to scale up the process with a view to build’human size’ thymi.”
Paola Bonfanti, senior author and group leader at the Crick and professor in the Division of Infection and Immunity at UCL says:”As well as providing a fresh source of transplants for people without a working thymus, our work has other possible future applications.
“For example, since the thymus helps the immune system to recognise self from non-self, it poses a problem for organ transplants as it can cause the immune system to attack the transplant.
“It’s possible that we could overcome this by also transplanting a thymus regrown from cells taken from the thymus of the organ donor. We are confident that this may prevent the body attacking the transplant. The research behind this is still in early days, but it’s an exciting concept which could remove the need for patients to take immune suppressors for the remainder of their life.
The researchers are continuing their work rebuilding thymi to refine and scale up the procedure.
The Francis Crick Institute
