ESPE Abstracts

The pituitary gland dynamically remodels during key timepoints of life to meet the prevailing endocrine demands of the organism. Mechanisms underlying this plasticity remain poorly understood. In particular, it is not clear how the pituitary stem cells are involved and biologically behave during pituitary remodeling processes. Indeed, pituitary stem cells remain highly enigmatic regarding cellular complexity, regulatory circuits, niche make-up and functional role. In our studies, we decode the pituitary stem cells’ biology at key physiological stages of life and during pathological conditions including local damage and tumorigenesis. To this end, we apply state-of-the-art single-cell transcriptomics and innovative pituitary-derived organoids, in vitro models closely recapitulating the stem cells’ biology. Single-cell RNA-sequencing (scRNA-seq) unraveled a high activation modus in the stem cell compartment of the neonatal maturing (mouse) pituitary. Transgenically inflicted local damage, although not inducing extra stem cell activation, is efficiently and fully restored. In contrast, injury at adult age promptly stimulates the pituitary stem cells and is also repaired, although more slowly and incomplete. scRNA-seq and organoid interrogation uncovered interleukin-6 (IL-6) as pituitary stem cell activator, being upregulated after the inflicted damage. At aging, the gland’s regenerative capacity fades, coinciding with absence of stem cell activation and IL-6 upsurge following the local injury, attributed to a pronounced inflammatory state in the older gland (i.e. ‘inflammaging’). Captivatingly, inquiry of human pituitary omics datasets showed significant translational power of our mouse-based findings. Also, the organoid models closely recapitulated the stem cells’ phenotypical and functional aspects according to specific age and pathology. Intriguingly, organoid examination revealed that the old pituitary’s stem cells retain intrinsic functionality but are in vivo restrained by the obstructive inflammatory microenvironment. Finally, we found that stem cell activation as occurring in the tumorigenic (mouse) gland is also recapitulated in organoid culture, comparable to findings in human pituitary tumor-derived organoids. Taken together, using innovative approaches we are cracking the pituitary stem cell code across life and pathologies. The resultant pituitary single-cell atlas will uncover stem cell complexity and pathways regulating stem cell behavior in the (remodeling) gland. Our endeavor can eventually translate into therapeutic, regenerative and rejuvenative strategies to counter deficient pituitary function due to damage, disease or aging.