The adaptive immune system depends upon the thymus. Thymocyte cells are generated in the bone marrow and then migrate to the thymus, where they mature into T cells through a complex process of training and selection. The thymus is largest during development, up until the end of childhood. At that point it shrinks dramatically, and then the remainder undergoes a slow atrophy over the rest of a lifespan. In older people, the much reduced volume of active thymic tissue diminishes the supply of new T cells, leading to an adaptive immune system increasingly made up of broken, misconfigured, exhausted, and senescent cells.
Finding ways to regrow the thymus is an ongoing endeavor, a number of companies taking a variety of approaches. Some are looking for small molecules to trigger regulatory genes governing thymic activity; some intend to deliver cells that home to the thymus and encourage new growth; gene therapies have been explored, involving a search for ways to target delivery systems to the thymus; and researchers are investigating the construction of new thymic tissue for transplant. You may be familiar with the work of Lygenesis and associated scientists in building thymus organoids that can be transplanted into lymph nodes.
Today’s open access paper is an example of this last sort of work, focused on being able to build thymic organoids from induced pluripotent stem cells. This offers the possibility of universal thymic tissues, built from cell lines engineered to prevent graft rejection, that could be transplanted into any patient. Or the more costly option of patient-matched thymic tissue, grown from their own cells. Clearly there is much more work to be done in order to build an artificial thymus that matches the natural thymus in structure and function, but the progress to date is promising.
Generation of functional thymic organoids from human pluripotent stem cells
The thymus is required for the development of a functional adaptive immune system, facilitating the generation of self-tolerant T cells that can respond to foreign antigens. Thymic epithelial cells (TECs) are divided into cortical and medullary (c/m) TECs, based on their location and function. Age-related involution of the thymus results in decreased thymic function and naive T cell output and increased autoimmunity and disease risk.
Thymic organoids cultured at the air-liquid interface allow for the interrogation of thymic function and T cell development. Functional human reaggregated thymic organoid cultures (RTOCs) made with expanded 1° TECs and thymic mesenchyme (TM) combined with allogenic cord blood-derived hematopoietic stem cells (HSCs) support T cell development in vitro and in vivo. However, RTOCs depend on 1° tissue access, are allogeneic, and do not support negative selection.
Recently, we reported the directed differentiation of induced PSCs (iPSC) to functional thymic epithelial progenitors (TEPs) that support murine T cell development after transplantation in nude mice. While differentiation of TEPs from human iPSCs has been demonstrated by multiple groups, in vitro generation of functional TECs has yet to be achieved. We sought to develop a thymic organoid model with isogenic hPSC-derived cell compartments that supports patient-specific TEC and T cell development in vitro.
We combined hPSC-derived TEPs, hematopoietic progenitor cells (HPCs), and mesenchymal cells to generate functional isogenic stem cell-derived thymic organoids (sTOs). sTOs support TEC development as demonstrated by HLA-DR, CD205, KRT5, and autoimmune regulator (AIRE) expression after 2-4 weeks in vitro, even in the absence of HPCs. AIRE, HLA-DR, and tissue-restricted antigen (TRA) expression suggests the potential for negative selection in this system. Importantly, sTOs support T cell development, including some regulatory T cells (Tregs). For the first time, to our knowledge, we demonstrate the generation of functional hPSC-derived TECs in vitro.