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Regenerating adrenal glands in a petri dish — ScienceDaily

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Located on top of the kidneys, the adrenal glands play a key role in keeping the body healthy. Responding to signals from the brain, the gland secretes hormones that support important functions such as blood pressure, metabolism, and fertility.

People with adrenal diseases such as primary adrenal insufficiency, in which the gland does not secrete enough hormones, can suffer from fatigue, dangerously low blood pressure, coma and even death if left untreated. There is no cure for primary adrenal insufficiency, and the lifelong hormone replacement therapy used to treat it has significant side effects.

A preferred alternative would be a regenerative medicine approach, restoring a functional adrenal gland capable of synthesizing hormones and releasing them appropriately in response to feedback from the brain. With new research in the journal Cell developmentresearchers at the University of Pennsylvania School of Veterinary Medicine have induced stem cells in a petri dish to divide, mature and take over some of the functions of a human fetal adrenal gland, bringing that goal one step closer.

“This is proof that we can create a system grown in a dish that functions almost identically to the human adrenal gland at early stages of development,” says Kotaro Sasaki, senior author and assistant professor at Penn Vet. “A similar platform can be used to better understand the genetics of adrenal insufficiency and even to screen for drugs to determine the best therapy 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 many different cell types, to mimic the stages of normal human adrenal development. During this process, the cells will be directed to take on the characteristics of the adrenal glands.

To begin, the researchers used a system known as “organoid culture” in which cells are grown first as a floating aggregate for three weeks, then on a membrane exposed to air on one side, which promotes better survival and allows them to reproduce after three weeks . dimensions. Using a carefully selected growth medium, they induced iPSCs to give rise to an intermediate tissue type in adrenal development, the posterior intermediate mesoderm (PIM).

After verifying that they had cultured PIM-like cells, the researchers began to direct these cells to the next stage, similar to adrenocortical progenitor cells, during which the cells incorporate markers that indicate they are “promised” to become adrenal cells.

Molecular assays to test for adrenal markers, as well as transmission electron microscope analysis, told Sasaki and his colleagues that they were on the right track to recreating tissue that resembled early adrenal glands.

“The process we developed was very efficient: about 50% of the cells in the organoids acquired the fate of adrenal cortical cells,” says Michinori Mayama, a postdoctoral fellow in Sasaki’s lab and lead author of the study. “The ovoid cells with bulky pink cytoplasm and relatively small nuclei that we saw in our cultures are very typical of human adrenal cells at this stage.”

Sasaki, Miyama, and the rest of the research team performed a series of tests to assess how well the functionality of the cells they cultured matched that of human adrenal glands. They found that lab-grown cells produced steroid hormones, such as DHEA, just like the “real-life” equivalent. “In vitro, we can produce many of the same steroids that are produced in vivo,” Mayama says.

They also showed that the cells they grew could respond to the so-called hypothalamic-pituitary-adrenal axis, a feedback loop that regulates communication from the brain to the adrenal glands and back. “We used drugs that normally suppress the adrenal gland’s production of DHEA and showed that our iPSC-derived adrenal cells responded similarly to these drugs, markedly reducing hormone production,” says Sasaki. “This means you can use this system to screen for drugs that target adrenal hormone production, which could benefit patients with overproduction of adrenal hormones or prostate cancer that uses adrenal hormones for its growth.”

The researchers are refining their system and say they hope to create more gradations in the type of tissue that occurs in mature adult adrenal glands.

Such a platform opens up opportunities to learn much more about the still mysterious adrenal gland. In particular, Sasaki notes that it could be used to study the genetic basis of adrenal insufficiency, as well as other diseases such as adrenal carcinoma. Ultimately, the approach used to create this gland in a dish may one day work to restore a functioning feedback loop between the brain and adrenal glands in people with adrenal disease.

“This is the first study of its kind,” says Sasaki. “The field of cell therapy is promising for the treatment of not only adrenal insufficiency, but also other hormonal diseases: hypertension, Cushing’s syndrome, polycystic ovary syndrome and others.”

Kotaro Sasaki is an assistant professor of biomedical sciences at the University of Pennsylvania School of Veterinary Medicine.

Michinori Mayama is a postdoctoral fellow in the Department of Biomedical Sciences at Penn Vet.

Sasaki and Mayama were co-authored by Yuka Sakata, Keren Cheng, and Yasunari Seita of Penn Vet; Penn Medicine’s Andrea Detlefsen, Clementina A. Mesaras, Trevor M. Penning, Wenli Yang, and Jerome F. Strauss III; Kyosuke Shishikura of the Pennsylvania Department of Chemistry; and Richard J. Aukus from the University of Michigan. Sakata, Cheng and Mayama were among the authors of the study. Sasaki was the senior author.

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

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