Thymus Regeneration and Future Challenges

Abstract

Thymus regenerative therapy implementation is severely obstructed by the limited number and expansion capacity in vitro of tissue-specific thymic epithelial stem cells (TESC). Current solutions are mostly based on growth factors that can drive differentiation of pluripotent stem cells toward tissue-specific TESC. Target-specific small chemical compounds represent an alternative solution that could induce and support the clonal expansion of TESC and reversibly block their differentiation into mature cells. These compounds could be used both in the composition of culture media designed for TESC expansion in vitro, and in drugs development for thymic regeneration in vivo. It should allow reaching the ultimate objective - autologous thymic tissue regeneration in paediatric patients who had their thymus removed in the course of cardiac surgery.

Keywords: Small chemical compounds; Stem cells; Thymectomised patients; Thymic epithelial stem cells; Thymus; Thymus regeneration.

Fig. 1.

Human thymus cell architecture. The human thymus is located in the upper anterior part of the chest behind the sternum between lungs and lies on top of the heart along the trachea. The thymus reaches its maximum weight (about 28 gram) during puberty. This pinkish-gray organ consists of two lobes parted into lobules by connective tissue strands (trabeculae). Each thymic lobule has a cortex and medulla. Hematopoietic precursor cells (HPC) enters the thymus through postcapillary venules located at the corticomedullary junction (CMJ) and migrate to the capsule, committed CD4-CD8- T precursor cells (TPC) located in the subcapsular region, and immature CD4+CD8+ cortical thymocytes migrate through the cortex and CMJ to the medullar zone. The medulla contains CD4+ and CD8+ naïve thymocytes that will migrate to the periphery. The stromal-epithelial compartment of the thymus is represented by minor populations of EpCam+(CD326+)Foxn1+ bipotent thymic epithelial precursor cells/thymic epithelial stem cells (TEPC/TESC) and mesenchymal stem cells (MSC) located probably in the thymic parenchyma close to the CMJ region, as well as EpCam+CD205+ cortical thymic epithelial cells (cTEC) located in the cortex and EpCam+Air+ medullary thymic epithelial cells (mTEC) located in the medulla. Moreover, the cortex and the medulla contain also macrophages, fibroblasts and dendritic cells (DC) that together with cTEC and mTEC participate in the differentiation, maturation, positive and negative selection of thymocytes. HPC generate all thymocyte populations and alternatively may generate macrophages and DC; TEPC/TESC generate cTEC and mTEC lineages depending on local microenvironment and cross-talk with cortical or medullary thymocytes; MSC generate thymic fibroblasts and adipocytes. BV: Blood vessel; DT: Dead thymocyte; HC: Hassall’s corpuscle.

Fig. 2.

TESC/SCC-based strategy for thymus regenerative therapy in partially thymectomized infants. Thymic epithelial stem cell/Small chemical compound (TESC/SCC)-based strategy for autologous thymus regenerative therapy in infants could include the development of clinical grade protocols for collection, preparation and cryopreservation of primary infant thymic tissue and TESCenriched samples. These TESC could be used further to screen SCC for regulation, differentiation and proliferation of human TESC. The selected compounds would be tested for clonal expansion of TESC in vitro and for the reconstitution of thymic function in vivo in terms of maturation, differentiation and tolerance of autologous T cells as well as for supporting thymus tissue growth. Finally, full pharmacological evaluation of the properly selected and optimised compounds would be performed for high efficacy and low toxicity and further drug development. An actual challenge is the optimization of thymectomy procedure in infants to preserve a thymic fragment for consequent postsurgical thymus regenerative therapy. An additional impact on the efficacy of the post-surgical rehabilitation may provide the quality life monitoring of thymectomized patients in relation to their resistance to infections, allergies, autoimmune, oncological and other diseases associated with the impaired thymic function.