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Tissue-Engineered Thymus (Wake Forest Institute for Regenerative Medicine)

Tissue-Engineered Thymus

Principal Investigator: John Jackson

Research Team: Silvia Gutierrez, Shruti Singh, Shay Soker, James Yoo

The thymus gland is responsible for the development of a class of immune cells called T-cells. As part of the degenerative aging process, the thymus shrinks in size, and the structure and function of the remaining tissue decays, with the critical thymic epithelial tissues responsible for maturing T-cells giving way to fat cells and collagen. This process of “thymic atrophy” prevents the body from maturing new T-cells, progressively weakening the body’s ability to fight off never-before-encountered infections. Engineering new, healthy thymic tissue would help to restore the vigorous immune response of youth.

SENS Research Foundation is therefore funding this WFIRM group to apply tissue engineering techniques to the creation of functional thymic tissue to fortify or replace the aging thymus. Engineering new tissues requires a “scaffold” in which to embed cells to give them structure and functional cues, and the WFIRM group is testing two different scaffolding systems: decellularized donor scaffolds and hydrogels.
In the decellularized scaffold paradigm, an organ of the type that is needed is taken from a donor, but is then stripped of its original cells and DNA, leaving behind a protein structure that can be repopulated with cells taken from the new organ recipient. This results in a new organ with the native structure and growth factors already present in the transplanted original organ, but with all the cells and most of the DNA and proteins of the recipient, eliminating the potential for immune rejection. The WFIRM group have been testing out different protocols for stripping donor material from scaffolds, and have so far determined that different methods yield different effects on the growth and the specialization of the cells that are seeded into them. They have also found that an intermediate concentration of epithelial cells gives the best growth and attachment, yielding cells with cell-surface markers specific to both important types of thymic epithelial cells. Upcoming studies will evaluate whether these elementary organs can support the development of bone marrow progenitor cells into early-stage T-cells.
In the hydrogel approach, cell aggregates are cultured in a 3D collagen-based hydrogel system. Hydrogel scaffolds resemble soft tissues more closely than any other purely human-made structure, and are highly biocompatible, making them unlikely to trigger an immune or rejection response. To generate the cells to seed into the hydrogel scaffold, the WFIRM group cultured thymus epithelial cells and bone marrow progenitor cells in microscopic wells that encouraged them to cluster together into spherical structures. These spheroids were then placed in a basic hydrogel scaffold, where they have so far remained viable for several weeks at a time. During the first three weeks, small numbers of mature T-cells begin to develop from the bone marrow stem cells. These early organ-like systems are now being observed to see how well the hydrogels support the development of new thymic epithelial cells.