Thymus Degeneration and Regeneration

The immune system’s ability to resist the invasion of foreign pathogens and the tolerance to self-antigens are primarily centered on the efficient functions of the various subsets of T lymphocytes. As the primary organ of thymopoiesis, the thymus performs a crucial role in generating a self-tolerant but diverse repertoire of T cell receptors and peripheral T cell pool, with the capacity to recognize a wide variety of antigens and for the surveillance of malignancies. However, cells in the thymus are fragile and sensitive to changes in the external environment and acute insults such as infections, chemo- and radiation-therapy, resulting in thymic injury and degeneration. Though the thymus has the capacity to self-regenerate, it is often insufficient to reconstitute an intact thymic function. Thymic dysfunction leads to an increased risk of opportunistic infections, tumor relapse, autoimmunity, and adverse clinical outcome. Thus, exploiting the mechanism of thymic regeneration would provide new therapeutic options for these settings. This review summarizes the thymus’s development, factors causing thymic injury, and the strategies for improving thymus regeneration.

The BMMSCs Derived From Juvenile Macaques Have the Ability to Promote Thymus Regeneration in Aged Macaques

BackgroundThe thymus gland is an important central immune organ in the human body and plays an indispensable role in the immune system. Aging thymic atrophy is critical factors leading to immune function decline and senile debilitation in aged people. Immune function decline is one of the important mechanisms of aging. Some research reports indicated that Stem cell therapy have the ability to promote tissue regeneration，but reverse thymus atrophy or promote atrophy thymus regenerate by stem cells need to be confirmed further. MethodsThe elderly macaque models were systematic screened and the thymus structure and function were evaluated by imaging and histopathology methods. The juvenile BMMSCs were injected into macaque models body by intravenous infusion. The effects of thymus tissue structure and expression of related factors were investigated by using imaging, histopathology,cell and molecule observation and measurement techniques. To explore the mechanism of juvenile BMMSC on thymus atrophy in aging rhesus macaques, the gene transcription profile of thymus tissue were sequencing and analyzed by bioinformatic methods. .ResultsThrough PET-CT observation, the thymus tissue density gradually increased after treatment, CT value gradually increased, SUVmax >1;The percentage of CD3+T cells in peripheral blood increased first and then decreased, CD3+CD4+T cells increased slowly, and CD3+CD8+T cells increased first, then decreased and then increased. By detecting Tregs in peripheral blood, the percentage of Tregs in peripheral blood showed a trend of decreasing first and then increasing after treatment (P< 0.05).The levels of thymosin α and thymosin II in peripheral blood were analyzed by ELISA method. It was found that thymosin α was firstly increased and then decreased after BMSC infusion, and the levels of thymosin Ⅱ were firstly increased and then decreased.The area of thymus parenchyma increased, and the boundary between skin and medulla appeared. Some thymus tissues were regenerated and changed to normal structure.The cortical and medullary junction structure and dense thymus structure gradually appeared in the elderly treatment group.The degree of thymus tissue fibrosis was reduced, and the deposition of collagen fiber was reduced. Apoptosis cells decreased significantly in the elderly treatment group compared with the elderly group. BMMSCs inhibited the expression of genes related to aging and apoptosis.ConclusionTransplantation BMMSC derived from juvenile macaques can poromote thymus regeneration, reverse thymus atrophy by regulating gene transcription profiles in aged macaques.

Thymus Regeneration Is Dependent on Distinct Mesenchymal Stromal Cell Populations

Background The regenerative ability of the thymus is an important factor in determining the outcome of bone marrow transplantation. However, the currently employed cytoreductive regimens invariably damage the thymic stroma, thus impeding recovery of T lymphopoiesis. Additionally, the thymic niche is poorly defined. Thymic epithelial cells have been extensively characterized, but our understanding of how other stromal cell types contribute to T lymphopoiesis is limited. We therefore set out to further define the thymic niche under homeostasis and regeneration. Results Using single-cell RNA-sequencing, we demonstrated that the thymic stromal cell compartment is composed of 10 stromal cell subsets. A specific subset of periostin expressing mesenchymal stromal cells (Postn+ MSCs) were found to be enriched in T cell promoting factors such as BMP2, BMP4, Ccl19 and Flt3 ligand (Fig. 1A). To elucidate the functional role of Postn+ MSCs in thymus regeneration, thymic stromal cells were isolated 3 days post-irradiation and transplantation and sequenced. Although the subsets classified as MSC generally persist following irradiation, the Postn+ MSCs were significantly reduced at a time when thymus seeding progenitors typically enter the tissue (Fig 1B). The secretion of chemokines and cytokines was also found to be faulty in the Postn+ MSC subset following transplantation, including significant reductions in Bmp2 and Cxcl14 (Fig 1C). In addition, there was a significant increase in a separate class of pro-adipogenic MSCs (Fig 1B), suggesting that the slow regeneration of the thymus after a transplantation could in part be due to this imbalance in MSC subtypes. Testing this hypothesis, thymic MSC subsets were adoptively transferred into irradiated and transplanted hosts. Specific subsets increased influx of thymocyte progenitors and aided in endothelial cell recovery (Fig 1D) consistent with regeneration of the thymic microenvironment. Furthermore, the transferred MSCs persisted and improved T cell numbers in the circulation up to 16 weeks post-transplantation (Fig 1E). To further investigate the clinical relevance of the MSC compartment, single-cell RNA-sequencing was performed on thymus stromal cells from human samples. Similarly, to what was observed in the murine tissue, human Postn+ MSC were found to express high levels of CCL19 and BMP4. Conclusion These data indicate that specific mesenchymal cell subsets in the thymus are important mediators of thymus regeneration. Moreover, adoptive transfer of MSC subsets may enable improved T cell recovery in the setting of bone marrow transplantation and perhaps other settings of T cell deficiency. Disclosures Scadden: Novartis: Other: Sponsored research; Bone Therapeutics: Consultancy; Magenta Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Editas Medicine: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fog Pharma: Consultancy; Red Oak Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Consultancy, Equity Ownership; Clear Creek Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; LifeVaultBio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.