Pituitary Regeneration: It'll Knock Your SOX Off!

Tissue regeneration provides promise for improved treatments for many human pathologies affecting neural and cardiac tissues, pancreas, bone, and cochlear hair cells (1–5). Recent studies in the pituitary gland have demonstrated that although cell turnover is normally low, pituitary stem cells do exist and can regenerate pituitary endocrine cell types in response to physiological stressors (6, 7). Increasing our understanding of and ability to manipulate pituitary regeneration is important for improving therapeutics for patients with hypopituitarism. Pituitary stem cells reside primarily in the marginalzone, a layer of cells bordering the pituitary cleft, and express several stem cell markers, including sex-determining region Y box 2 (SOX2) (6, 8, 9). Additional stem cell niches may exist in the pituitary gland as a subset of SOX2 cells are scattered throughout the anterior pituitary (6, 7, 10, 11). Deletion of Sox2 causes severe pituitary hypoplasia and reduced differentiation of somatotropes and thyrotropes due to insufficient renewal of periluminal stem cells (12). Additional evidence for the presence of pituitary stem cells comes from studies showing that SOX2 pituitary cells from embryos and adults have the ability to differentiate into multiple pituitary endocrine cell types in culture and in vivo, suggesting that these cells are multipotent (8, 13). In this issue of Endocrinology, an elegant study by Willems et al (33) provides insight into pituitary regeneration. Previously, this group used a transgenic mouse model (GHCre/iDTR) to target somatotropes for ablation by diphtheria toxin (DT) (14). Treatment with DT for 3 days obliterated nearly all somatotropes. In young adult mice, somatotropes were able to regenerate, and somatotrope populations were partially restored. The process of regeneration involved expansion of the SOX2 marginal-zone niche and the appearance of cells doubly positive for cytoplasmic SOX2 and GH, which likely represent cells transitioning from progenitors to terminally differentiated somatotropes (14). In the current study, Willems et al (33) expand their investigation by addressing the role of recovery period and age in regenerative capacity. Using the same model (GHCre/iDTR), they demonstrate that increasing the recovery period to 19 months does not significantly increase restoration of somatotrope numbers. Interestingly, after ablation of somatotropes in older mice, regeneration no longer occurrs, suggesting that regenerative capacity of the pituitary gland is lost with age. The loss of regenerative capacity in older animals correlates with a significant reduction in stem cells, especially those containing nuclear SOX2. Thus, nuclear SOX2 may be an indicator of healthy stem cells that are able to contribute to regenerative capacity. To determine how pituitary stem cells respond to extended ablation of somatotropes, Willems et al (33) treated young GHCre/iDTR mice with DT for 10 days. Interestingly, they find that somatotrope regeneration does not occur under these conditions, suggesting that continual ablation of somatotropes exhausts regenerative capacity of stem cells in young adult pituitary glands. Stem cell exhaustion has been observed in other systems as well. Deletion of the forkhead transcription factor family members, Foxo1, Foxo3, and Foxo4, in neural stem cells of mice results in aberrant proliferation and increased brain size. The excessive proliferation of neural stem cells eventually leads to exhaustion of their regenerative capacity ultimately causing a reduction in neural stem cells and neural degeneration (15). These data suggest that regulation of proliferation is important for maintaining stem cell health and regenerative capacity. Similar results were observed with deletion of Foxo family members in hemato-