Embryonic Development and Adult Regeneration of the Adrenal Gland

Abstract

The adrenal gland plays a pivotal role in an organism's health span by controlling the endocrine system. Decades of research on the adrenal gland have provided multiscale insights into the development and maintenance of this essential organ. A particularly interesting finding is that founder stem/progenitor cells participate in adrenocortical development and enable the adult adrenal cortex to regenerate itself in response to hormonal stress and injury. Since major advances have been made in understanding the dynamics of the developmental process and the remarkable regenerative capacity of the adrenal gland, understanding the mechanisms underlying adrenal development, maintenance, and regeneration will be of interest to basic and clinical researchers. Here, we introduce the developmental processes of the adrenal gland and discuss current knowledge regarding stem/progenitor cells that regulate adrenal cortex remodeling and regeneration. This review will provide insights into the fascinating ongoing research on the development and regeneration of the adrenal cortex.

Keywords: Adrenal cortex; Adrenal glands; Developmental biology; Regeneration; Stem cells.

Fig. 1

The establishment of the adrenal gland. In the embryonic stage, following the growth of adrenogonadal primordium (AGP) on both sides, the adrenal progenitor population on the medial side of the AGP and the gonadal progenitor population on the lateral side of the AGP separate to form the adrenal primordium (AP) and the gonadal primordium (GP), respectively. From 6 weeks post-conception (wpc), the neural crest cells that later become the adrenal medulla invade the AP and the mesenchymal cells that become the capsule encapsulate them to establish the fetal adrenal gland. The enlarged fetal zone (FZ) is gradually replaced by the outer definitive zone (DZ). After birth, the FZ regresses through apoptosis and the adrenal cortex starts the zonation of the DZ into the zona glomerulosa (zG) and zona fasciculate (zF). Among the three major cortical zones, the zona reticularis (zR) is the last to develop. At around 6 to 8 years old, a period known as adrenarche, the zR is formed in the cortical-medullary boundary of the adrenal cortex. The production of adrenal androgens is clearly observed from this stage onwards. Unlike humans, the adrenal cortex in mice exhibits the X-zone as a transient cortical compartment at the cortical–medullary boundary. The regression of the X-zone is sexually dimorphic.

Fig. 2

Homeostasis, renewal, and regeneration of the adult adrenal cortex. To carry out the unique endocrine functions of the adrenal gland, three major compartments in the adrenal cortex, as well as the medulla, are controlled by external regulatory factors. Under the regulation of the renin-angiotensin system, the zona glomerulosa (zG) produces aldosterone to adjust the levels of sodium and potassium ions in plasma. In response to the circulating adrenocorticotropic hormone (ACTH) from the pituitary gland, the zona fasciculate (zF) and zona reticularis (zR) synthesize cortisol (corticosterone in mice) and adrenal androgens (dehydroepiandrosterone [DHEA] and dehydroepiandrosterone sulfate [DHEAS]), respectively. These steroids are governed by the hypothalamic-pituitary-adrenal (HPA) axis according to hormonal demands and external stress. The adrenocortical stem/progenitor cells in the capsule and sub-capsule regions of the adrenal cortex centripetally replenish senescent steroidogenic cells to maintain healthy steroidogenic cells in the cortical layer. The sonic hedgehog (SHH) and Wnt signaling pathway reciprocally regulate each type of signaling activity, and this mutual relationship is critical for maintaining proper functions of the adrenal cortex. ACTH-protein kinase A (PKA) signaling contributes to differentiating progenitors into steroidogenic cells in the zF. The adrenal cortical regeneration rates in males and females are similar to those of dihydrotestosterone (DHT)-treated females and gonadectomized (GDX) males, respectively, which explains the inhibitory effect of androgens on glioma-associated oncogene homolog 1+ (GLI1+) stem cell recruitment, and sexual dimorphism in the adrenal regeneration [36]. WT1, Wilms’ tumor 1; SF1, steroidogenic factor 1; GFP, green fluorescent protein; 20αHSD, 20α-hydroxysteroid dehydrogenase; CYB5, cytochrome B5; CC3, cleaved caspase 3.