Endocrinol Metab.  2020 Dec;35(4):765-773. 10.3803/EnM.2020.403.

Embryonic Development and Adult Regeneration of the Adrenal Gland

Affiliations
  • 1School of Biological Sciences, Seoul National University, Seoul, Korea
  • 2Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Korea

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.

Keyword

Adrenal glands; Adrenal cortex; Developmental biology; Regeneration; Stem cells

Figure

  • 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.


Cited by  1 articles

Clinical and Technical Aspects in Free Cortisol Measurement
Man Ho Choi
Endocrinol Metab. 2022;37(4):599-607.    doi: 10.3803/EnM.2022.1549.


Reference

1. Yates R, Katugampola H, Cavlan D, Cogger K, Meimaridou E, Hughes C, et al. Adrenocortical development, maintenance, and disease. Curr Top Dev Biol. 2013; 106:239–312.
Article
2. Ross IL, Louw GJ. Embryological and molecular development of the adrenal glands. Clin Anat. 2015; 28:235–42.
Article
3. Walczak EM, Hammer GD. Regulation of the adrenocortical stem cell niche: implications for disease. Nat Rev Endocrinol. 2015; 11:14–28.
Article
4. Pihlajoki M, Dorner J, Cochran RS, Heikinheimo M, Wilson DB. Adrenocortical zonation, renewal, and remodeling. Front Endocrinol (Lausanne). 2015; 6:27.
Article
5. Finco I, Mohan DR, Hammer GD, Lerario AM. Regulation of stem and progenitor cells in the adrenal cortex. Curr Opin Endocr Metab Res. 2019; 8:66–71.
Article
6. Freedman BD, Kempna PB, Carlone DL, Shah M, Guagliardo NA, Barrett PQ, et al. Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev Cell. 2013; 26:666–73.
Article
7. King P, Paul A, Laufer E. Shh signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci U S A. 2009; 106:21185–90.
Article
8. Else T, Hammer GD. Genetic analysis of adrenal absence: agenesis and aplasia. Trends Endocrinol Metab. 2005; 16:458–68.
Article
9. Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell. 1994; 77:481–90.
Article
10. Kim AC, Barlaskar FM, Heaton JH, Else T, Kelly VR, Krill KT, et al. In search of adrenocortical stem and progenitor cells. Endocr Rev. 2009; 30:241–63.
Article
11. Goto M, Piper Hanley K, Marcos J, Wood PJ, Wright S, Postle AD, et al. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J Clin Invest. 2006; 116:953–60.
Article
12. Hanley NA, Rainey WE, Wilson DI, Ball SG, Parker KL. Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: potential interactions in gene regulation. Mol Endocrinol. 2001; 15:57–68.
Article
13. Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev. 1997; 18:378–403.
Article
14. Mesiano S, Coulter CL, Jaffe RB. Localization of cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17 alpha-hydroxylase/17, 20-lyase, and 3 beta-hydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation. J Clin Endocrinol Metab. 1993; 77:1184–9.
Article
15. Ishimoto H, Jaffe RB. Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocr Rev. 2011; 32:317–55.
Article
16. Michelsohn AM, Anderson DJ. Changes in competence determine the timing of two sequential glucocorticoid effects on sympathoadrenal progenitors. Neuron. 1992; 8:589–604.
Article
17. Yoshida-Hiroi M, Bradbury MJ, Eisenhofer G, Hiroi N, Vale WW, Novotny GE, et al. Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice. Mol Psychiatry. 2002; 7:967–74.
Article
18. Anderson DJ, Carnahan JF, Michelsohn A, Patterson PH. Antibody markers identify a common progenitor to sympathetic neurons and chromaffin cells in vivo and reveal the timing of commitment to neuronal differentiation in the sympathoadrenal lineage. J Neurosci. 1991; 11:3507–19.
Article
19. Reissmann E, Ernsberger U, Francis-West PH, Rueger D, Brickell PM, Rohrer H. Involvement of bone morphogenetic protein-4 and bone morphogenetic protein-7 in the differentiation of the adrenergic phenotype in developing sympathetic neurons. Development. 1996; 122:2079–88.
Article
20. Wilburn LA, Goldsmith PC, Chang KJ, Jaffe RB. Ontogeny of enkephalin and catecholamine-synthesizing enzymes in the primate fetal adrenal medulla. J Clin Endocrinol Metab. 1986; 63:974–80.
Article
21. Kim AC, Reuter AL, Zubair M, Else T, Serecky K, Bingham NC, et al. Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex. Development. 2008; 135:2593–602.
22. Wood MA, Acharya A, Finco I, Swonger JM, Elston MJ, Tallquist MD, et al. Fetal adrenal capsular cells serve as progenitor cells for steroidogenic and stromal adrenocortical cell lineages in M. musculus. Development. 2013; 140:4522–32.
23. Wiener D, Smith J, Dahlem S, Berg G, Moshang T Jr. Serum adrenal steroid levels in healthy full-term 3-day-old infants. J Pediatr. 1987; 110:122–4.
Article
24. Kojima S, Yanaihara T, Nakayama T. Serum steroid levels in children at birth and in early neonatal period. Am J Obstet Gynecol. 1981; 140:961–5.
Article
25. Nakamura Y, Gang HX, Suzuki T, Sasano H, Rainey WE. Adrenal changes associated with adrenarche. Rev Endocr Metab Disord. 2009; 10:19–26.
Article
26. Jia X, Sun C, Tang O, Gorlov I, Nambi V, Virani SS, et al. Plasma dehydroepiandrosterone sulfate and cardiovascular disease risk in older men and women. J Clin Endocrinol Metab. 2020; 105:dgaa518.
Article
27. Rendina DN, Ryff CD, Coe CL. Precipitous dehydroepiandrosterone declines reflect decreased physical vitality and function. J Gerontol A Biol Sci Med Sci. 2017; 72:747–53.
Article
28. Howard-Miller E. A transitory zone in the adrenal cortex which shows age and sex relationships. Am J Anat. 1927; 40:251–93.
Article
29. Hershkovitz L, Beuschlein F, Klammer S, Krup M, Weinstein Y. Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone. Endocrinology. 2007; 148:976–88.
30. Guasti L, Cavlan D, Cogger K, Banu Z, Shakur A, Latif S, et al. Dlk1 up-regulates Gli1 expression in male rat adrenal capsule cells through the activation of β1 integrin and ERK1/2. Endocrinology. 2013; 154:4675–84.
Article
31. Quinn TA, Ratnayake U, Dickinson H, Nguyen TH, McIntosh M, Castillo-Melendez M, et al. Ontogeny of the adrenal gland in the spiny mouse, with particular reference to production of the steroids cortisol and dehydroepiandrosterone. Endocrinology. 2013; 154:1190–201.
Article
32. Salmon TN, Zwemer RL. A study of the life history of cortico-adrenal gland cells of the rat by means of trypan blue injections. Anat Rec. 1941; 80:421–9.
Article
33. Zwemer RL, Wotton RM, Norkus MG. A study of corticoadrenal cells. Anat Rec. 1938; 72:249–63.
Article
34. Deane HW, Greep RO. A morphological and histochemical study of the rat’s adrenal cortex after hypoph ysectomy, with comments on the liver. Am J Anat. 1946; 79:117–45.
35. Ingle DJ, Higgins GM. The extent of regeneration of the enucleated adrenal gland in the rat as influenced by the amount of capsule left at operation. Endocrinology. 1939; 24:379–82.
Article
36. Grabek A, Dolfi B, Klein B, Jian-Motamedi F, Chaboissier MC, Schedl A. The adult adrenal cortex undergoes rapid tissue renewal in a sex-specific manner. Cell Stem Cell. 2019; 25:290–6.
Article
37. Ching S, Vilain E. Targeted disruption of Sonic Hedgehog in the mouse adrenal leads to adrenocortical hypoplasia. Genesis. 2009; 47:628–37.
Article
38. Huang CC, Miyagawa S, Matsumaru D, Parker KL, Yao HH. Progenitor cell expansion and organ size of mouse adrenal is regulated by sonic hedgehog. Endocrinology. 2010; 151:1119–28.
Article
39. Vokes SA, Ji H, McCuine S, Tenzen T, Giles S, Zhong S, et al. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development. 2007; 134:1977–89.
Article
40. Finco I, Lerario AM, Hammer GD. Sonic hedgehog and WNT signaling promote adrenal gland regeneration in male mice. Endocrinology. 2018; 159:579–96.
Article
41. Heikkila M, Peltoketo H, Leppaluoto J, Ilves M, Vuolteenaho O, Vainio S. Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology. 2002; 143:4358–65.
Article
42. Mandel H, Shemer R, Borochowitz ZU, Okopnik M, Knopf C, Indelman M, et al. SERKAL syndrome: an autosomal-recessive disorder caused by a loss-of-function mutation in WNT4. Am J Hum Genet. 2008; 82:39–47.
Article
43. Vidal V, Sacco S, Rocha AS, da Silva F, Panzolini C, Dumontet T, et al. The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3. Genes Dev. 2016; 30:1389–94.
44. Lotfi CF, de Mendonca PO. Comparative effect of ACTH and related peptides on proliferation and growth of rat adrenal gland. Front Endocrinol (Lausanne). 2016; 7:39.
Article
45. Clark BJ. ACTH action on StAR biology. Front Neurosci. 2016; 10:547.
Article
46. Hofland J, Delhanty PJ, Steenbergen J, Hofland LJ, van Koetsveld PM, van Nederveen FH, et al. Melanocortin 2 receptor-associated protein (MRAP) and MRAP2 in human adrenocortical tissues: regulation of expression and association with ACTH responsiveness. J Clin Endocrinol Metab. 2012; 97:E747–54.
Article
47. Clark AJL, Chan L. Stability and turnover of the ACTH receptor complex. Front Endocrinol (Lausanne). 2019; 10:491.
Article
48. Novoselova TV, Hussain M, King PJ, Guasti L, Metherell LA, Charalambous M, et al. MRAP deficiency impairs adrenal progenitor cell differentiation and gland zonation. FASEB J. 2018; 32:fj201701274RR.
Article
49. Gondo S, Yanase T, Okabe T, Tanaka T, Morinaga H, Nomura M, et al. SF-1/Ad4BP transforms primary long-term cultured bone marrow cells into ACTH-responsive steroidogenic cells. Genes Cells. 2004; 9:1239–47.
Article
50. Yazawa T, Mizutani T, Yamada K, Kawata H, Sekiguchi T, Yoshino M, et al. Differentiation of adult stem cells derived from bone marrow stroma into Leydig or adrenocortical cells. Endocrinology. 2006; 147:4104–11.
Article
51. Yazawa T, Kawabe S, Inaoka Y, Okada R, Mizutani T, Imamichi Y, et al. Differentiation of mesenchymal stem cells and embryonic stem cells into steroidogenic cells using steroidogenic factor-1 and liver receptor homolog-1. Mol Cell Endocrinol. 2011; 336:127–32.
Article
52. Gondo S, Okabe T, Tanaka T, Morinaga H, Nomura M, Takayanagi R, et al. Adipose tissue-derived and bone marrow-derived mesenchymal cells develop into different lineage of steroidogenic cells by forced expression of steroidogenic factor 1. Endocrinology. 2008; 149:4717–25.
Article
53. Crawford PA, Sadovsky Y, Milbrandt J. Nuclear receptor steroidogenic factor 1 directs embryonic stem cells toward the steroidogenic lineage. Mol Cell Biol. 1997; 17:3997–4006.
Article
54. Zubair M, Oka S, Parker KL, Morohashi K. Transgenic expression of Ad4BP/SF-1 in fetal adrenal progenitor cells leads to ectopic adrenal formation. Mol Endocrinol. 2009; 23:1657–67.
55. Wang Q, Lan Y, Cho ES, Maltby KM, Jiang R. Odd-skipped related 1 (Odd 1) is an essential regulator of heart and urogenital development. Dev Biol. 2005; 288:582–94.
56. Nishinakamura R, Matsumoto Y, Nakao K, Nakamura K, Sato A, Copeland NG, et al. Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development. Development. 2001; 128:3105–15.
57. Val P, Martinez-Barbera JP, Swain A. Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. Development. 2007; 134:2349–58.
Article
58. Clipsham R, Niakan K, McCabe ER. Nr0b1 and its network partners are expressed early in murine embryos prior to steroidogenic axis organogenesis. Gene Expr Patterns. 2004; 4:3–14.
Article
59. Kim J, Koo BK, Knoblich JA. Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol. 2020; 21:571–84.
Article
60. Ho BX, Pek NMQ, Soh BS. Disease modeling using 3D organoids derived from human induced pluripotent stem cells. Int J Mol Sci. 2018; 19:936.
Article
Full Text Links
  • ENM
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr