Adrenocortical zonation, renewal, and remodeling

Abstract

The adrenal cortex is divided into concentric zones. In humans the major cortical zones are the zona glomerulosa, zona fasciculata, and zona reticularis. The adrenal cortex is a dynamic organ in which senescent cells are replaced by newly differentiated ones. This constant renewal facilitates organ remodeling in response to physiological demand for steroids. Cortical zones can reversibly expand, contract, or alter their biochemical profiles to accommodate needs. Pools of stem/progenitor cells in the adrenal capsule, subcapsular region, and juxtamedullary region can differentiate to repopulate or expand zones. Some of these pools appear to be activated only during specific developmental windows or in response to extreme physiological demand. Senescent cells can also be replenished through direct lineage conversion; for example, cells in the zona glomerulosa can transform into cells of the zona fasciculata. Adrenocortical cell differentiation, renewal, and function are regulated by a variety of endocrine/paracrine factors including adrenocorticotropin, angiotensin II, insulin-related growth hormones, luteinizing hormone, activin, and inhibin. Additionally, zonation and regeneration of the adrenal cortex are controlled by developmental signaling pathways, such as the sonic hedgehog, delta-like homolog 1, fibroblast growth factor, and WNT/β-catenin pathways. The mechanisms involved in adrenocortical remodeling are complex and redundant so as to fulfill the offsetting goals of organ homeostasis and stress adaptation.

Keywords: adrenal cortex; hormone; plasticity; stem cell; steroid; steroidogenesis.

Figure 1

Steroidogenic pathways in the human adrenal cortex and gonads.

Figure 2

Electron microscopy of mouse adrenal cortex. Adrenal glands from a 4-month-old female mouse were fixed in Karnovsky’s solution, postfixed in 2% OsO₄, dehydrated, and then embedded in epon. Thin sections were stained with uranyl acetate plus lead citrate and examined by transmission electron microscopy. (A) Adrenal capsule and zona glomerulosa. (B) Zona fasciculata. Abbreviations: c, capsule; e, endothelial cell; zF, zona fasciculata cell; zG, zona glomerulosa cell. Bars, 4 μm.

Figure 3

Comparative anatomy and physiology of the adrenal cortex. The undifferentiated zone of the rat adrenal is subdivided into outer (dark gray) and inner (light gray) zones that differ in marker expression and function (see the text). Abbreviations: cap, capsule; med, medulla; X, X-zone; zF, zona fasciculata; zG, zona glomerulosa; zI, zona intermedia; zR, zona reticularis; zU, undifferentiated zone.

Figure 4

Development of the adrenal gland and gonads.

Figure 5

Adrenocortical zonation during postnatal mouse development results from lineage conversion of zG cells into zF cells, as evidenced by fate mapping using Cyp11b2-cre and a GFP reporter. Recombination of the reporter in zG leads to expression of GFP (green cells). The resultant cells migrate inward and differentiate into zF cells. Abbreviations: cap, capsule; med, medulla; X, X-zone; zF, zona fasciculata; zG, zona glomerulosa.

Figure 6

GLI1⁺ cells in the adrenal capsule. An adrenal gland from a 1-month-old female Gli1-lacZ mouse was whole mount stained with X-gal, cryosectioned, and counterstained with eosin. Bar, 50 μm.

Figure 7

SHH and DLK1 are co-expressed in the outer zU of the rat adrenal cortex and may act in concert to regulate stem/progenitor cells in the adrenal capsule. Abbreviations: cap, capsule; DLK1, delta-like homolog-1; med, medulla; SHH, sonic hedgehog; X, X-zone; zF, zona fasciculata; zG, zona glomerulosa; zU, undifferentiated zone.

Figure 8

Immunoperoxidase staining of β-catenin in the adrenal cortex of a 2-month-old female mouse. Abbreviations: cap, capsule; zF, zona fasciculata; zG, zona glomerulosa; Bar, 30 μm.

Figure 9

WT1 marks a population of AGP-like progenitors within the adrenal capsule of the mouse. Under basal conditons, AGP-like cells give rise to normal steroidogenic cells in the cortex, as evidenced by lineage tracing analysis with a GFP reporter. Gonadectomy (GDX) triggers the differentiation of AGP-like cells into wedges of gonadal-like steroidogenic tissue. Secretion of sex steroids and other hormones by the ectopic gonadal tissue causes regression of the subjacent X-zone. Abbreviations: cap, capsule; med, medulla; X, X-zone; zF, zona fasciculata; zG, zona glomerulosa.

Figure 10

GATA6 is required for formation of a secondary X-zone. (A,B) 3-week-old Sf1-cre; Gata6^flox/+ or Sf1-cre; Gata6^flox/flox mice were orchiectomized. Adrenal tissue was harvested 1 month later, and paraffin sections were stained with H&E. Note the absence of a secondary X-zone in the mutant mice. The asterisk highlights gonadal-like cells in the subcapsular region. Bar, 50 μm.