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  • Review Article
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Adrenocortical stem cells in health and disease

Nature Reviews Endocrinology volume 21, pages 464–481 (2025)Cite this article

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An Author Correction to this article was published on 11 April 2025

This article has been updated

Abstract

The adrenal cortex is the major site of production of steroid hormones, which are essential for life. The normal development and homeostatic renewal of the adrenal cortex depend on capsular stem cells and cortical progenitor cells. These cell populations are highly plastic and support adaptation to physiological demands, injury and disease, linking steroid production and adrenal (organ) homeostasis with systemic endocrine cues and organismal homeostasis. This Review integrates findings from the past decade, outlining the mechanisms that govern the establishment and maintenance of the adrenal stem cell niche under different physiological and pathological conditions. The sophisticated regulation of the stem cell niche by gene regulatory networks, coordinated through paracrine and endocrine signalling, is highlighted in a context-dependent and sex-specific manner. We discuss how dysregulation of this intricate regulatory network is implicated in a wide range of adrenal diseases, and how emerging knowledge from adrenal stem cell research is inspiring the future development of gene-based and cell-based therapeutic strategies.

Key points

  • The adrenal cortex synthesizes and secretes vital steroid hormones necessary for maintaining physiological (organismal) homeostasis.

  • The adrenocortical stem cell niche comprises undifferentiated, non-steroid-producing capsular stem cells spatially juxtaposed to non-steroidogenic cortical progenitors.

  • Adrenocortical stem and progenitor cells display remarkable functional plasticity that links paracrine-mediated (SHH–WNT relay), intra-adrenal (organ) homeostasis with systemic endocrine-mediated (organismal) homeostasis.

  • Aberrations in components of the WNT or SHH signalling pathways contribute to a number of adrenal disorders, including some types of adrenal neoplasia and primary adrenal insufficiency.

  • A better understanding of the cellular and molecular mechanisms underlying the physiology and pathophysiology within the stem cell niche could inform the development of gene-based and cell-based regenerative therapeutic strategies.

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Fig. 1: Adrenal homeostasis is regulated by the interaction of paracrine and endocrine signalling cascades.
Fig. 2: Stages of adrenal development at tissue, cellular and molecular levels.
Fig. 3: Therapies targeting adrenal stem and progenitor cells to treat monogenic diseases.

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Acknowledgements

J.W. was supported by the Clinician Scientist program RISE, funded by the Else-Kröner-Fresenius-Stiftung and Eva Luise und Horst Köhler Stiftung.

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  1. These authors contributed equally: Yulan Chu, Jordan Setayesh.

Authors and Affiliations

  1. Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA

    Yulan Chu & Gary D. Hammer

  2. Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA

    Jordan Setayesh

  3. Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA

    Typhanie Dumontet, Johanna Werner, Isabele F. Moretti, Kelly De Sousa, Christopher La Pensee, Antonio M. Lerario & Gary D. Hammer

  4. Department of Surgery, University of Michigan, Ann Arbor, MI, USA

    Lauren Krumeich

  5. Division of Endocrinology and Diabetology, Department of Internal Medicine I, University Hospital of Wuerzburg, Wuerzburg, Germany

    Johanna Werner

  6. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA

    Christopher Kennedy & Gary D. Hammer

  7. Endocrine Oncology Program, Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Gary D. Hammer

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Contributions

G.H., Y.C., J.S., T.D., J.W. and I.F.M. contributed to all aspects of the article. L.K., K.D.S. and C.K. researched data for the article, contributed substantially to discussion of the content and wrote the article. C.L.P. reviewed and/or edited the manuscript before submission. A.L. contributed substantially to discussion of the content.

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Chu, Y., Setayesh, J., Dumontet, T. et al. Adrenocortical stem cells in health and disease. Nat Rev Endocrinol 21, 464–481 (2025). https://doi.org/10.1038/s41574-025-01091-2

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