When a gland is lost: an integrative biology approach to the study and modulation of thymus regeneration and its medical implications

The thymus, a key organ in adaptive immunity, is vital in the foetus but not after birth when involution begins, supporting the paradigm that its function ends in adult life. However, thymectomy may increase susceptibility to cancer, metabolic and inflammatory disorders, and clinical evidence suggests that the thymus remains active despite atrophy and shows striking regeneration after damage (infections or chemotherapy).

We hypothesise that studying the regrowth of the involuted human thymus after injury and in disease will unravel the mechanistic basis of regeneration. To this aim, we will develop a cross-disciplinary approach that moves from clinical samples to in vivo mouse models, through cutting-edge in vitro technologies. Our unexpected discovery of multipotent epithelial stem cells (SCs) in paediatric and adult thymi paved a new way to study thymus regeneration. We will 1) elucidate the molecular profile of involuted and injured thymi and the role of SCs by single cell and spatial transcriptomics; 2) investigate temporal dynamics and molecular mechanisms determining SC fate decision in vitro to identify molecular drivers through single cell transcriptomics and machine learning; 3) determine the thymic peptidome and functional innervation to reposition the thymus at the crossroad of the immune-neuroendocrine axis; 4) test molecules/pathways identified in aims 1-3 for modulation of differentiation in a combinatorial in vitro screening platform. Selected modulators will be validated in physiologically relevant in vitro 3D constructs and in humanised and transgenic mouse models.

Our multi-disciplinary and integrated approach will elucidate how thymus regeneration affects disease progression and will provide crucial insights to modulate regeneration in aged and injured thymi. This, in turn, will have a transformative impact on several conditions such as cancer and other chronic disorders, as well as congenital and acquired immunodeficiency and autoimmunity