Stem Cells of the Hypothalamic-Pituitary-Adrenal Axis.

Endocrine tissues must continuously adjust their structure and function in response to circadian cues, metabolic state, and physiological stress. Within these dynamic systems, stem cells contribute not only to tissue maintenance and repair but also to functional plasticity. The hypothalamic-pituitary-adrenal (HPA) axis exemplifies this integration of local stem cell regulation with systemic endocrine control. In this Review, we highlight the shared regulatory principles and tissue-specific adaptations of stem cell populations across the hypothalamus, anterior pituitary and adrenal gland. We discuss tanycytes as hypothalamic stem cells, SOX2+ stem cells as key regulators of pituitary plasticity, and multipotent and lineage-restricted progenitors that sustain adrenal cortical and medullary renewal. Across HPA axis organs, conserved signaling pathways and multiple modes of cell-cell communication, including paracrine and feedback mechanisms, coordinate stem cell behavior with endocrine output. Importantly, we present growing evidence that endocrine stem cells influence organ function beyond direct cell replacement, shaping tissue responsiveness, and adaptation to physiological demand. Disruption of these processes contributes to endocrine dysfunction and tumorigenesis. Integrating insights from genetic models, human single-cell and spatial atlases, we outline how viewing the HPA axis as an integrated stem cell system provides a framework for understanding endocrine plasticity and identifies emerging opportunities and challenges for regenerative and therapeutic strategies.