Stress tested, testing stress: Novel organoid models how the adrenal gland develops

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Sitting above each kidney are two small endocrine glands about the size of walnuts. These are the adrenal glands, responsible for producing hormones that help control some of the body’s most critical functions.

Among these hormones, cortisol is particularly critical for survival. Often referred to as the “stress hormone,” it helps the body adapt to a wide range of challenges—both emotional and physical, such as trauma or infection—by regulating overall metabolism.

Despite its central role in stress and endocrine biology, how the adrenal gland is built and how it functions remains poorly understood.

Now, researchers led by Kotaro Sasaki and Michinori Mayama of the School of Veterinary Medicine have developed a lab-grown organoid system that recapitulates the complex tissue structure, development, and function of the developing human adrenal cortex—the outer layer of the adrenal gland—providing a powerful platform to study its biology. These results, published in Cell Stem Cell, help establish a foundation for regenerative therapies targeting adrenal diseases.

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“The adrenal cortex is a major endocrine organ and central to our stress response,” says Sasaki, the Richard King Mellon Associate Professor of Biomedical Sciences. “Despite its importance, adrenal biology has lagged behind that of other organs. Our goal was to create a mini adrenal gland in a dish to better understand how the human adrenal forms and begins to function.”

The adrenal gland develops into multiple specialized layers, each with distinct functions, he explains, making it particularly challenging to recreate in a dish.

Previously, Sasaki and colleagues used human induced pluripotent stem cells—adult cells reprogrammed to become early embryonic cells capable of giving rise to many cell types—to develop a preliminary adrenal organoid system. But it lacked key functional features, including the ability to produce cortisol.

In this study, the team took a step-by-step approach, reconstructing early stages of human adrenal development. They identified how different cell populations interact to form the gland, including signals from the capsule—a thin layer of connective tissue surrounding the adrenal—that are essential for establishing the progenitor cells that give rise to the hormone-producing tissue.

Using a preclinical model, they showed that when these cell types were combined, the cells self-organized into a layered, 3D structure resembling the developing adrenal gland. Importantly, the organoid was functional: It produced cortisol and androgens in response to adrenocorticotropic hormone, a key signal from the brain that regulates stress responses.

“This means we can model how the adrenal gland responds to stress signals in a controlled setting,” says Michinori Mayama, a research associate in Sasaki’s lab.

The system also has implications for disease. In conditions such as primary adrenal insufficiency (e.g., Addison’s disease), the body cannot produce enough cortisol. Current treatment relies on lifelong hormone replacement, which does not fully replicate natural hormone rhythms and can lead to complications.

“Our results suggest that this organoid approach may open the door to an entirely new type of treatment—cell replacement therapy,” says Mayama. “This could one day transform a lifelong dependence on steroids into a one-time curative therapy—the holy grail for patients with primary adrenal insufficiency.”

But the potential for the system extends beyond better therapeutic options for adrenal insufficiency, says Sasaki.

“We can use this to better understand the biology of the human adrenal gland,” he says. “Right now, the adrenal glands are basically inaccessible—deep inside the body.”

But this system provides direct access, he notes, enabling researchers to genetically or pharmacologically manipulate the adrenal gland and study, at the cellular and molecular levels, how it is built, how it produces cortisol in response to stress, and how disease develops.

This accessibility also allows researchers to test drugs more easily, adds Mayama. “Because the organoids can be generated in large numbers, they may also serve as a platform for drug discovery, including screening compounds for disorders such as Cushing’s syndrome, which involves excess cortisol production.”

Looking ahead, they plan to continue to refine their organoid system, focusing on recreating a more mature stage of development, including the formation of adrenal cells that produce aldosterone, a hormone critical for blood pressure regulation.

“There are many diseases associated with aldosterone—like hypertension, which affects millions of people,” says Sasaki. “Our next goal is to build a more complete adrenal model to better understand and eventually treat these conditions.”

Kotaro Sasaki is the Richard King Mellon Associate Professor of Biomedical Sciences at the School of Veterinary Medicine and an associate professor in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania.

Michinori Mayama is a research associate in the Sasaki lab.

Other authors are Adrian N. Leu, Takeshi Sato, and Eoin C. Whelan from Penn Veterinary Medicine; Jerome F. Strauss III from Penn Medicine; and Richard J. Auchus and David G. Stouffer from the University of Michigan.

This work was supported in part by a Japan Society for the Promotion of Science Overseas Research Fellowship to M. Mayama; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (1R01DK134493 [note: this grant did not support studies involving prenatal human specimens]); Open Philanthropy funds from the Silicon Valley Community Foundation and the Good Ventures Foundation; the Quinlivan Family Foundation; and an IRM Translational Project Award from the Marda Foundation to K.S.