From autonomous hormone‐secreting cells to a plastic cellular architecture: How signaling builds and remodels the anterior pituitary

Abstract

The anterior pituitary was long understood through a “one hormone–one cell type” lens. Each endocrine cell was thought to answer autonomously to a dedicated hypothalamic secretagogue under hierarchical command. This view treats the gland's cellular makeup as a fixed backdrop to secretion. Five decades of work have replaced it with a self‐organizing, plastic cellular architecture. Its organization and composition are themselves built and continually remodeled by cell–cell and developmental signaling. We follow how this signaling wires the gland, specifies its composition, senses changing demand, and remodels the proportions of cells to maintain organismal homeostasis. Intercellular signaling organizes secretory cells into spatially structured, three‐dimensional homotypic and heterotypic networks, whether it is gap‐junctional, paracrine, or juxtacrine. Beyond wiring, signaling builds tissue cellular architecture. Developmental patterning pathways, several retained postnatally, set each cell type's proportions. These proportions then remodel with reproductive state, injury, end‐organ feedback, and age, down to the level of single‐cell states. A non‐endocrine compartment of folliculostellate/SOX2‐positive cells threads through the network as both a signaling conduit and a stem cell niche, and its role in proportioning the gland is demand‐dependent. At steady state, it acts mainly as a paracrine regulator while differentiated cells renew themselves. Under challenge, it becomes a source of new cells and mounts a broad, non‐selective expansion of cell mass. Lineage‐committed precursors then read this expansion against axis‐specific feedback to select which lineage the mass becomes, as established for corticotropes and proposed for the other axes. The review closes on the open problems that remain: how glandular composition is specified, sensed, and selected, and the methods best placed to resolve it.