Adrenal Reconstitution in a Petri Dish – ScienceDaily


The adrenal gland, located above the kidneys, plays a pivotal role in maintaining a healthy body. In response to signals from the brain, the gland secretes hormones that support vital functions such as blood pressure, metabolism, and fertility.

People with disorders of the adrenal glands, such as primary adrenal insufficiency, in which the gland does not secrete enough hormones, can experience fatigue, dangerously low blood pressure, coma, and even death if they are not treated. There is no cure for primary adrenal insufficiency, and the lifelong hormone replacement therapy used to treat it carries significant side effects.

A better alternative might be a regenerative medicine approach, regrowth of a functional adrenal gland capable of adequately synthesizing and releasing hormones in line with brain feedback. With a new study in the journal developmental cellResearchers from the University of Pennsylvania College of Veterinary Medicine coaxed stem cells in a petri dish to divide, mature and take over some of the functions of the human embryonic adrenal gland, bringing that goal one step closer.

“This is evidence that we can create a system growing in a dish that functions almost identically to the human adrenal gland in the early stages of development,” says Kotaro Sasaki, senior author and assistant professor at Penn Vet. “A platform like this could be used to better understand the genetics of adrenal insufficiency and even screen medications to determine which treatments are best for people with these disorders.”

Sasaki says his team’s goal was to use human induced pluripotent stem cells (iPSCs), which can give rise to a myriad of different cell types, to mimic the stages of normal human adrenal development. During this process, the cells are directed to take on the characteristics of the adrenal gland.

First, the researchers used what’s known as an “organic culture” system, in which cells grow first as a floating mass for three weeks, then on a membrane exposed to air on one side, which enhances survival and allows them to multiply in three dimensions. Using a carefully selected growth medium, they drove iPSCs to grow an intermediate type of tissue in the process of adrenal development, the posterior mesoderm (PIM).

After verifying that they had cultured PIM-like cells, the researchers proceeded to instruct those cells to move on to the next stage, adrenocortical-like cells, in which the cells turn on signs that they are “committed” to becoming adrenal cells.

They all told Sasaki and his colleagues that they are on track to recreate early adrenal gland-like tissue.

“The process we developed was highly efficient, with about 50% of cells in the organelle gaining an adrenocortical cell fate,” says Michinori Mayama, a postdoctoral researcher in Sasaki’s lab and lead author of the study. “The oval cells with the bulky pink cytoplasm and relatively small nuclei that we saw in our cultures are a very distinctive feature of human adrenal cells at that stage.”

Sasaki and Mayama and the rest of the research team ran a number of tests to assess how closely the function of the cells they transplanted closely matched that of the human adrenal gland. They found that cells grown in the lab produce steroid hormones, such as DHEA, just as the “real-life” equivalent does. “In the lab, we can produce many of the same steroids that are produced in vivo,” says Mayama.

They also showed that the cells he grew could respond to what’s known as the hypothalamic-pituitary-adrenal axis, a feedback loop that controls communication from the brain to the adrenals and back again. “We used drugs that inhibit DHEA production in the adrenal glands and showed that iPSC-derived adrenal cells respond similarly to these drugs, with a significant decrease in hormone production,” says Sasaki. “This means that you can use this system to screen drugs that target adrenal hormone production, which could benefit patients with adrenocorticism or those with prostate cancer that exploits adrenal hormones for their growth.”

As the researchers improve their system, they say they hope they can generate more gradients in the type of tissue that occur in the adult adrenal gland.

Such a platform opens up opportunities to learn more about the still-mysterious adrenal gland. In particular, Sasaki points out that it could be useful for examining the genetic basis of adrenal insufficiency as well as other diseases, such as adrenal cancer. Ultimately, the approach to creating this gland in a dish may one day recreate the feedback loop between the brain and adrenals in people with adrenal disorders.

“This is the first study of its kind,” says Sasaki. “The field of cell therapy holds a lot of promise for treating not only adrenal insufficiency but other hormone-driven diseases: high blood pressure, Cushing’s syndrome, PCOS, and more.”

Kotaro Sasaki is an Assistant Professor in the Department of Biomedical Sciences at the University of Pennsylvania College of Veterinary Medicine.

Michinori Mayama is a postdoctoral fellow in the Department of Biomedical Sciences at the University of Pennsylvania.

Sasaki and Mayama’s authors were Ben Vets, Kirin Cheng, and Yasunari Seita. Andrea Detlefsen of Penn Medicine, and Clementina A. Mesaros, Trevor M Benning, Wenli Yang, and Jerome F. Strauss III; Kyosuke Shichikura of the University of Pennsylvania Department of Chemistry; and Richard J. Oshos of the University of Michigan. Sakata, Cheng, and Mayama were the first to participate in the study. Sasaki was a lead author.

The study was supported in part by the Silicon Valley Community Foundation (Grant 2019-197906) and Good Ventures (Grant 10080664).



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