Regulation of the adrenocortical stem cell niche: implications for disease

Abstract

Stem cells are endowed with the potential for self-renewal and multipotency. Pluripotent embryonic stem cells have an early role in the formation of the three germ layers (ectoderm, mesoderm and endoderm), whereas adult tissue stem cells and progenitor cells are critical mediators of organ homeostasis. The adrenal cortex is an exceptionally dynamic endocrine organ that is homeostatically maintained by paracrine and endocrine signals throughout postnatal life. In the past decade, much has been learned about the stem and progenitor cells of the adrenal cortex and the multiple roles that these cell populations have in normal development and homeostasis of the adrenal gland and in adrenal diseases. In this Review, we discuss the evidence for the presence of adrenocortical stem cells, as well as the various signalling molecules and transcriptional networks that are critical for the embryological establishment and postnatal maintenance of this vital population of cells. The implications of these pathways and cells in the pathophysiology of disease are also addressed.

Figure 1

Cell lineages in adrenal gland development and homeostasis. a | Cell lineages contributing to the adrenal gland. The catecholamine-producing cells of the adrenal medulla (purple) are derived from neural crest precursors. WT1-expressing mesenchymal cells (orange) contribute to the adrenal capsule. Fetal adrenal cells (dark pink) give rise to a subpopulation of Gli1-expressing capsular cells. Gli1⁺ capsular cells give rise to undifferentiated SHH-secreting cells (green) and differentiated steroidogenic adrenocortical cells (blue) of the adult gland. WT1-expressing cells give rise to differentiated cells of the adult cortex that no longer express WT1. b | Adrenal gland development begins when the AGP forms and separates into a fetal gonad (not shown) and a fetal adrenal gland. Cells from the neural crest infiltrate the fetal adrenal gland to form the medulla, while mesenchymal cells participate in encapsulation. Fetal adrenal cells give rise to a portion of the adrenal capsule. As the definitive cortex grows and the fetal cortex regresses, Gli1⁺ capsular cells give rise to SHH-secreting progenitors and steroidogenic adrenocortical cells. WT1⁺ cells also contribute to the cortex, albeit infrequently. Postnatally, the capsular and subcapsular progenitor cells are retained throughout adulthood, during which time they maintain homeostasis of the definitive adrenal cortex. Abbreviations: AGP, adrenogonadal primordium; SHH, sonic hedgehog; WT1, Wilms tumour protein homolog. Adapted with permission from Wood, M. A. et al. Development 140 (22), 4522–4532 (2013) http://dx.doi.org/10.1242/dev.092775.

Figure 2

Simplified view of the adrenocortical homeostatic unit. The adrenal gland consists of the adrenal medulla (purple cells) and the adrenal cortex (blue concentric layers) that is encased within the adrenal capsule (orange circle). The adrenocortical capsule contains mesenchymal cells (dark orange) and stem cells (light orange). Adrenocortical stem cells give rise to undifferentiated, nonsteroidogenic adrenocortical progenitor cells (green cells) and differentiated, steroidogenic cells of the adrenal cortex (blue cells of various hues). Cells stream through the cortex until they reach the cortical–medullary boundary where they undergo apoptosis (grey cells).

Figure 3

Paracrine and endocrine signals that act on adrenocortical cells. Ang II and ACTH are endocrine signals that stimulate steroidogenesis in differentiated cells of the zona glomerulosa (dark blue cells, Ang II), the zona fasciculata (medium blue cells, ACTH) and the zona reticularis (light blue cells, ACTH), respectively. Undifferentiated progenitor cells (green cells) secrete SHH ligands that act on stem cells within the adrenal capsule (light orange cells). Wnt ligands are received by cells of the zona glomerulosa, are critical for maintenance of adrenocortical progenitors, and indirectly regulate aldosterone production (not shown). INHα maintains the adrenal (as opposed to gonadal) fate of progenitor cells. FGFs are secreted from and received by both the capsule and the cortex and might be involved in regulation of cell proliferation. During adulthood, IGFs are expressed in the capsule, act on the cortex to promote proliferation, and can participate in steroidogenesis. Abbreviations: ACTH, adrenocorticotropic hormone; Ang II, angiotensin II; FGF, fibroblast growth factor; IGF, insulin-like growth factor; INHα, inhibin-α; SHH, sonic hedgehog; Wnt, Wingless-type MMTV integration site.