Stem cells within the HPA axis in tissue homeostasis and disease

The hypothalamus-pituitary-adrenal (HPA) axis is crucial for energy metabolism, cardiovascular function, and stress response. Importantly, neuronal signaling circuits in the hypothalamus, along with hormones released from the pituitary and adrenal gland, must adapt to physiological demands or pathological conditions. Stem and progenitor cells are pivotal in this regulation, either by giving rise to distinct cell types or by interacting with progenitor or hormone-producing cells. While lineage-tracing studies in rodent models have explored the role of stem cells in the HPA axis, our understanding of the mechanisms underlying this dynamic tissue plasticity remains limited, especially in humans. Moreover, single-cell RNA sequencing has revealed significant heterogeneity among stem cell populations in the HPA-axis, raising questions about the functional relevance of individual subclusters during development and adulthood. In this concise review, we summarize current knowledge on stem cells in the HPA axis, focusing on their origins, localization of different stem cell populations, and sex-specific activity in maintaining tissue integrity. We further address their role under pathophysiological conditions, including metabolic disease, cancer, and stress. Lastly, we discuss emerging strategies for replacing lost or damaged stem or progenitor cells during aging, highlighting recent achievements in the in vitro differentiation of hypothalamic, pituitary, and adrenal stem cells.