Pituitary stem cell regulation: who is pulling the strings?

The pituitary gland plays a pivotal role in the endocrine system, steering fundamental processes of growth, metabolism, reproduction and coping with stress. The adult pituitary contains resident stem cells, which are highly quiescent in homeostatic conditions. However, the cells show marked signs of activation during processes of increased cell remodeling in the gland, including maturation at neonatal age, adaptation to physiological demands, regeneration upon injury and growth of local tumors. Although functions of pituitary stem cells are slowly but gradually uncovered, their regulation largely remains virgin territory. Since postnatal stem cells in general reiterate embryonic developmental pathways, attention is first being given to regulatory networks involved in pituitary embryogenesis. Here, we give an overview of the current knowledge on the NOTCH, WNT, epithelial-mesenchymal transition, SHH and Hippo pathways in the pituitary stem/progenitor cell compartment during various (activation) conditions from embryonic over neonatal to adult age. Most information comes from expression analyses of molecular components belonging to these networks, whereas functional extrapolation is still very limited. From this overview, it emerges that the 'big five' embryonic pathways are indeed reiterated in the stem cells of the 'lazy' homeostatic postnatal pituitary, further magnified en route to activation in more energetic, physiological and pathological remodeling conditions. Increasing the knowledge on the molecular players that pull the regulatory strings of the pituitary stem cells will not only provide further fundamental insight in postnatal pituitary homeostasis and activation, but also clues toward the development of regenerative ideas for improving treatment of pituitary deficiency and tumors.