Fight Aging!

Decellularization followed by recellularization is a well explored approach to tissue engineering. Researchers take a donor organ or tissue section, decellularize it to leave the intricate extracellular matrix and all of its chemical cues, and then recellularize with with the desired mix of cells. When those cells are derived from a patient, it is possible to generate tissue that can be transplanted into that patient with minimal risk of rejection. There are also groups working on enabling cross-species transplantation from pigs to humans via this strategy of replacing all of the cells in an organ with patient-matched cells.

Further, recellularization can bypass the major challenge of vascular network creation in tissue engineering. Natural tissues contain extensive capillary networks, hundreds of tiny blood vessels passing through every square millimeter of tissue cross-section. Without capillaries, tissue cannot be more than a millimeter or two in thickness, as cells will not be able to receive nutrients. Capillary networks have so far proven challenging to produce at the fine scale needed via bioprinting of entirely artificial tissue structures, though some inroads have been made in recent years. A decellularized extracellular matrix contains those capillaries already.

This is not to say that recellularization of a decelluralized tissue is straightforward. Just like the production of organoids, small functional organ tissue sections grown from cells, a recipe must be established, the right cell populations derived and introduced into the right places, in the right order, provided with the right supporting cues and nutrients, and so forth. This is different for each different type of organ tissue, and there are a great many organs worthy of interest.

Today's example is the production of a recellularized organ important to the immune system, the thymus. The thymus atrophies with age, but active thymic tissue is required for thymocytes created in the bone marrow to mature into T cells of the adaptive immune system. As the supply of new T cells diminishes with age, the adaptive immune system becomes ever more dysfunctional and damaged. The thymus is unfortunately deep within chest, and a straightforward transplantation is a more extensive surgery than would be desirable in later life. The researchers behind Lygenesis have demonstrated in animal models that thymic organoid tissue placed into much more accessible lymph nodes can function correctly, however. Since thymocytes already migrate to the thymus, moving (or even distributing) the thymus to other locations in the body is a possibility. It remains to be seen as to how the tissue engineering approaches to the challenge of thymic atrophy - and consequent immune dysfunction - will evolve in the years ahead, but producing functional thymic tissue is a necessary starting point.

Scientists build whole functioning thymus from human cells

Researchers have rebuilt a human thymus, an essential organ in the immune system, using human stem cells and a bioengineered scaffold. To rebuild this organ, the researchers collected thymi from patients and in the laboratory, 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 obtain a structural scaffold of thymi, which they could repopulate with the thymic cells they had cultured. For this, researchers developed a new approach to remove all the cells from rat thymi, so only the structural scaffolds remained. They had to use a new microvascular surgical approach for this, as conventional methods are not effective for the thymus.

The researchers then injected the organ scaffolds with up to six million human thymic epithelial cells as well as interstitial cells from the colonies they had grown in the lab. The cells grew onto the scaffolds and after only five days, the organs had developed to a similar stage as those seen in nine-week old foetuses. Finally, the team implanted these thymi into mice. They found that in over 75% of cases, the thymi were able to support the development of human lymphocytes. The researchers are continuing their work rebuilding thymi to refine and scale up the process.

Reconstitution of a functional human thymus by postnatal stromal progenitor cells and natural whole-organ scaffolds

The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice.