Almost identical adrenal glands to humans

A team of researchers at the University of Pennsylvania has successfully induced stem cells to exhibit the properties and functions of the human adrenal glands, an advance that could pave the way
for new therapies to treat adrenal insufficiency.

The adrenal glands are located above the kidneys and are essential
for maintaining overall health.
It produces hormones to regulate essential functions such as blood pressure, metabolism, and fertility in response to signals from the brain
.

People with adrenal gland disorders, such as primary adrenal insufficiency, where the glands do not produce enough hormones, and if left untreated, can experience symptoms
such as fatigue, low blood pressure, coma, and even death.
Currently, there is no cure for primary adrenal insufficiency, and hormone replacement therapy used for treatment has significant side effects
.

A better alternative is the regenerative medicine approach, which regenerates a functioning adrenal gland, capable of synthesizing hormones and releasing them
appropriately based on feedback from the brain.
In a new study published in the journal Developmental Cell, researchers at the University of Pennsylvania College of Veterinary Medicine brought that goal one step
closer by inducing stem cells to divide, mature, and have some of the functions of the adrenal glands of the human fetus in a petri dish.

"This is a proof of principle that we can create a system grown in a petri dish that, in the early stages of development, functions almost exactly like the human adrenal glands," said senior author Kotaro Sasaki, an assistant professor at the University of Pennsylvania College of Veterinary Medicine
.
"Such platforms could be used to better understand the genetics of adrenal insufficiency and could even be used for drug screening to find better treatments
for people with these conditions.
"

Sasaki says his team's goal is to mimic the stages of normal human adrenal development using human induced pluripotent stem cells (iPSCs), which can produce a myriad of different cell types
.
In this process, cells are directed out of the features of
the adrenal glands.

First, the researchers used a so-called "organoid culture" system, in which cells are first grown as floating aggregates for three weeks and then grown on a membrane exposed to air on one side, promoting better survival and allowing them to proliferate
in three-dimensional space.
Using carefully selected growth media, they prompted iPSCs to induce an intermediate tissue type, the post-mesomesoderm (PIM),
during adrenal development.

After confirming that they had grown PIM-like cells, the researchers began guiding the cells to the next stage, the adrenal cortex progenitor cell-like cells, during which the cells turned on markers indicating that they had "promised" to become adrenal cells
.

Molecular analysis examining adrenal markers, as well as transmission electron microscopy analysis, both told Sasaki and colleagues that they were on the right track to reconstruct tissues similar to the
early adrenal glands.

"The process we developed was so efficient that about 50 percent of the cells in the organoids acquired the fate of adrenal cortex cells," said
Michinori Mayama, a postdoc in Sasaki's lab and lead author of the study.
"The oval cells we see in culture have a large amount of pink cytoplasm and relatively small nuclei, which are very typical of
human adrenal cells at this stage.
"

Sasaki, Mayama and other members of the research team conducted a series of tests to assess how close
the function of the cells they cultured was to that of the human adrenal glands.
They found that lab-grown cells produced steroid hormones, such as DHEA, just like their "real-life" equivalents
.
"In vitro, we can produce most of the same steroids
that are produced in the body," Mayama said.

They also showed that the cells they grew could respond to the so-called hypothalamic-pituitary-adrenal axis, a feedback loop
that controls communication between the brain and the adrenal glands and returns.
"We used drugs that normally inhibit adrenal dehydroepiandrosterone production and showed that our iPSCs-derived adrenal cells responded similarly to these drugs, with significantly reduced
hormone production," Sasaki said.
This means that you can use this system to screen drugs that target adrenohormones, which may benefit patients with excessive adrenal hormone secretion or prostate cancer patients
who use adrenal hormones to promote growth.
”

As the researchers refine their system, they hope to be able to produce more hierarchies of tissue types, as happens in the adrenal glands of mature adults
.

Such a platform provides an opportunity
to learn more about the still mysterious adrenal glands.
In particular, Sasaki noted that it could be used to explore the genetic basis
of adrenal insufficiency, as well as other diseases such as adrenal cancer.
Eventually, the method used to create this "gland-in-the-dish" may one day recreate a functioning brain-adrenal feedback loop
in patients with adrenal gland disease.

Sasaki said, "This is an unprecedented study
.
The field of cell therapy holds promise for treating not only adrenal insufficiency, but also other hormone-driven diseases: hypertension, Cushing's syndrome, polycystic ovary syndrome, and many more
.
”

References "Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells" by Yuka Sakata, Keren Cheng, Michinori Mayama, Yasunari Seita, Andrea J.
Detlefsen, Clementina A.
Mesaros, Trevor M.
Penning, Kyosuke Shishikura, Wenli Yang, Richard J.
Auchus, Jerome F.
Strauss, and Kotaro Sasaki, 21 November 2022, Developmental Cell.

DOI: 10.
1016/j.
devcel.
2022.
10.
010