Cellular and Molecular Basis of de novo Thymus Regeneration
Final Report Abstract
The thymus is the primary site of T-cell development, essential for establishing selftolerance and supporting adaptive immune functions. In mammals, thymic involution occurs with age, leading to a global decline in immune responses and immunesenescence. While the mammalian thymus exhibits regenerative abilities, these exclusively rely on pre-existing remnants and are insufficient to counteract thymic atrophy. By studying the axolotl thymus, our study uncovered an exceptional exception to this rule: axolotls can regenerate their entire thymus from scratch, independent of any remnants, providing the first demonstration of whole-organ regeneration in a vertebrate organism. Specifically, our study demonstrated that the axolotl (Ambystoma mexicanum) can regenerate its thymus de novo after complete removal (i.e. full thymectomy), establishing a unique example among vertebrates. Using a combination of single-cell RNA sequencing, genetic manipulation and transplantation approaches, we uncovered that de novo thymus regeneration restores morphology, cellular diversity, and functionality. We also discovered that the transcription factor FoxN1, a well-known regulator of thymus development and function, is crucial for thymus organogenesis in the axolotl as it is in mammals, as its disruption leads to reduced size and lymphopoietic output. However, we find that FoxN1 is surprisingly dispensable for initiating de novo thymus regeneration. Instead, we identify a number of pathways that are necessary to achieve de novo thymus regeneration. Among them, we find that BMP and Midkine (MDK) signalling pathways are necessary to elicit this remarkable process. In particular, we identified Midkine as a critical early driver of de novo thymus regeneration. Moreover, bioinformatic analysis of thymus development in mouse and human at the single cell level revealed a hitherto unknown involvement of MDK in mediating stromal interactions during thymus development in both species, suggesting that Midkine may also be relevant to thymus development and regeneration in mammalian contexts. Together, our study unveiled a new mechanism of thymus regeneration, setting a foundation for future therapeutic interventions.
