Identification and characterisation of a novel SOX2+ stem cell population in the adrenal medulla

The adrenal glands are two major endocrine organs responsible for multiple physiological processes, including the stress response, modulating the immune system and metabolism. The adrenal is composed of an outer cortex and an inner medulla with distinct developmental origin and function. While tissue-specific stem/progenitor populations of the adrenal cortex have been widely identified and characterised, the presence of a functional stem/progenitor population in the medulla is unclear. Establishing cell hierarchy of the adrenal medulla essential to understand normal homeostasis, disease pathogenesis and establishing regenerative medicine strategies, therefore the identification of a stem/progenitor population would provide an important starting point for further basic and translational studies. Cell composition of the adrenal medulla includes three main cell types: chromaffin cells, which secrete catecholamines, neurons, which stimulate catecholamine production, and a third cell type with an unspecified “support” function called sustentacular cells. Using transcriptomics and genetic approaches in mouse, I established that a population of sustentacular cells express the stem/progenitor marker SOX2. These cells are present throughout life and have a developmental origin congruent with the rest of the gland. Through genetic lineage-tracing using the Sox2CreERT2 strain, I demonstrate that SOX2+ cells are an expanding population, capable of giving rise to the catecholamine-producing chromaffin cells, consistent with a stem cell role in vivo. I further demonstrate the self-renewal potential of SOX2+ cells through in vitro isolation and expansion, using a Sox2eGFP mouse line. Analysis of SOX2+ cells in physiological organ challenge suggests potential involvement of these cells in the response to perturbation of normal homeostasis. Through analysis of FFPE sections of human adrenals, I confirm the presence of SOX2+ cells in the normal adult organ, as well as in pheochromocytomas. Taken together, these data support the identification of a previously undescribed stem cell population in the mammalian adrenal medulla and confirm its functional relevance