Stem cell function and plasticity in the normal physiology of the adrenal cortex

Abstract

The adrenal cortex functions to produce steroid hormones necessary for life. To maintain its functional capacity throughout life, the adrenal cortex must be continually replenished and rapidly repaired following injury. Moreover, the adrenal responds to endocrine-mediated organismal needs, which are highly dynamic and necessitate a precise steroidogenic response. To meet these diverse needs, the adrenal employs multiple cell populations with stem cell function. Here, we discuss the literature on adrenocortical stem cells using hematopoietic stem cells as a benchmark to examine the functional capacity of particular cell populations, including those located in the capsule and peripheral cortex. These populations are coordinately regulated by paracrine and endocrine signaling mechanisms, and display remarkable plasticity to adapt to different physiological and pathological conditions. Some populations also exhibit sex-specific activity, which contributes to highly divergent proliferation rates between sexes. Understanding mechanisms that govern adrenocortical renewal has broad implications for both regenerative medicine and cancer.

Keywords: Adrenal homeostasis; Adrenocortical zonation; Sex-specific renewal; Sonic hedgehog; Stem cell function; Wnt/β-catenin.

Figure 1.. The adrenal cortex employs multiple cell populations with stem cell function to support cellular renewal.

The outer mesenchymal capsule contains distinct populations of multipotent stem cells, including GLI+ and WT1+ cells, which are capable of giving rise to steroidogenic cells. These populations contribute at relatively low rates to homeostatic adrenocortical renewal, but can be acutely activated in response to severe stress. The main driver of homeostatic centripetal renewal is the zona glomerulosa (zG), which is characterized by high Wnt pathway activation and the production of SHH ligands. The zG contains CYP11B2− cells as well as more differentiated CYP11B2+ cells, which can repopulate the inner cortex through transdifferentiation. The ability of the adrenal cortex to maintain cellular renewal through a diverse set of mechanisms enables the tissue to adapt to a wide range of physiological and pathological conditions.

Figure 2.. Reciprocal signaling between the capsule and cortex coordinately regulates SHH and Wnt pathway activation.

Schematic representation of the crosstalk between the mesenchymal capsule and underlying adrenal cortex that is required for SHH and Wnt activity. (Top) Adrenocortical cells in the glomerulosa produce SHH ligands, while capsular cells express the central components of the SHH signaling response, PTCH1 and SMO. In the absence of ligand, PTCH1 inhibits the activity of SMO. SHH ligand binding inactivates PTCH1 and subsequently derepresses SMO, which leads to intracellular signal transduction and the activation of GLI transcription factors. Additionally, PTCH1 and SMO are respectively dependent upon the transmembrane flux of sodium ions and cholesterol availability. (Bottom) Capsular-to-cortical signaling regulates Wnt pathway activation. RSPO3 produced by the capsule helps facilitate degradation of ZNRF3 in underlying adrenal cortex. ZNRF3 is a transmembrane E3 ubiquitin ligase that acts to promote the turnover of Wnt receptor complexes. Thus, RSPO3-mediated degradation of ZNRF3 potentiates Wnt pathway activation by increasing the availability of Wnt receptors on the cell surface. Schematic created with BioRender.com.

Figure 3.. Antagonism between Wnt/β-catenin and cAMP/PKA signaling helps determine adrenocortical cell fate.

Activation of Wnt/β-catenin signaling induces a transcriptional program that promotes zG differentiation, which includes several genes that support the production of aldosterone (e.x. Agtr1, Cyp11b2, Nr4a1, and Nr4a2). Simultaneously, Wnt/β-catenin activation represses zF identity through mechanisms that include direct up regulation of Pde2a. Conversely, cAMP/PKA signaling promotes zF differentiation by increasing expression of several genes that support the production of glucocorticoids (e.x. Mc2r, Cyp11b1, Star, Cyp11a1, and Akr1b7). PKA signaling additionally represses Wnt/β-catenin activation through mechanisms that include inhibition of Wnt4. The balance between Wnt and PKA signaling in part determines adrenocortical cell fate. Schematic created with BioRender.com.

Figure 4.. The zona glomerulosa displays heterogeneity and contains several populations that support adrenocortical renewal.

Wnt/β-catenin pathway activation, as measured by Axin2 and Wnt4 expression, follows a gradient in the normal adrenal cortex with highest pathway activation in the outermost cortex. Shh is expressed in the zona glomerulosa (zG) and a subset of more differentiated zG cells express Cyp11b2. Single-molecule in situ hybridizations were performed on serial sections from 6-week-old female mice as previously described. Representative images are shown. Scale bars, 100μm.