Developmental Cell: Recreate the adrenal glands in a petri dish

The adrenal glands are located above the kidneys on both sides and play a key role
in maintaining human health.
Glands secrete hormones based on signals from the brain that support key functions
such as blood pressure, metabolism and fertility.

Some people have problems with their adrenal glands, such as primary adrenal insufficiency (inability to release enough hormones), and if left untreated, they may experience fatigue, low blood pressure, coma, and even death
.
There is no cure for primary adrenal insufficiency, and lifelong hormone replacement therapy has significant side effects
.

A better option is a regenerative medicine approach, which regenerates an adrenal gland capable of synthesizing hormones and releasing the hormones
appropriately based on feedback from the brain.
Researchers at the University of Pennsylvania's School of Veterinary Medicine recently published their results
in the journal Developmental Cell.
They induced stem cell division and maturation in a petri dish and assumed some of the functions of the adrenal glands of the human fetus, one step
closer to the goal of adrenal gland regeneration.

Corresponding author Kotaro Sasaki, an assistant professor at the University of Pennsylvania's School of Veterinary Medicine, said: "This is a proof of principle that we can grow a system
in a petri dish that functions almost identically to the adrenal glands in early human development.
Such a platform could help us better understand adrenal insufficiency and even be used for drug screening to find better treatments
for patients with the disease.
”

Sasaki says their team's goal is to use human induced pluripotent stem cells (iPSCs) to mimic the stages
of normal adrenal development in humans.
During this process, these cells are directed and take on the characteristics of the
adrenal glands.

First, the researchers used an "organoid culture" system, in which cells are first grown as floating aggregates for three weeks and then on a biofilm exposed to air on one side for better survival and proliferation
in three dimensions.
They then used a select growth medium to develop iPSCs into an intermediate tissue type, the posterior mid-stage germ (PIM).

After confirming that they had cultured PIM-like cells, the researchers began guiding these cells to the next stage, the adrenal cortex progenitor cell-like cells
.
At this stage, cells express markers indicating that they have "decided" to become adrenal cells
.
After conducting molecular analysis and transmission electron microscopy, Sasaki and colleagues determined that they were on the right track
.

Michinori Mayama, a postdoc in Sasaki's lab, said: "The process we developed is very efficient, with about 50% of the cells in the organoids differentiating into adrenal cortex cells
.
The oval cells we saw in the culture had a large amount of pink cytoplasm and relatively small nuclei, which were characteristic of
human adrenal cells at that stage.
”

The researchers also conducted a series of tests to assess how similar
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 dehydroepiandrosterone (DHEA), just like hormones produced "in real life
.
" "In vitro, we can produce the same steroids as in the body," Mayama said
.

They also showed that cultured cells could respond to the hypothalamic-pituitary-adrenal axis, a feedback loop
that controls communication between the brain and the adrenal glands.
"We used drugs that normally inhibit adrenal DHEA production, and the results showed that iPSC-derived adrenal cells responded to these drugs with significantly reduced hormone production," Sasaki said
.
"This means that you can use this system to screen drugs that target adrenal hormone secretion, which will hopefully benefit
patients with excessive adrenal hormone secretion.
"

As researchers continue to improve their system, they hope to be able to produce more layers of tissue types, much like the mature adult adrenal glands
.
Sasaki notes that it could help people explore the genetic basis of adrenal insufficiency and other diseases, such as adrenal cancer
.
Ultimately, this method of making glands in petri dishes promises to recreate a functioning brain-adrenal feedback loop
in patients with adrenal gland disease.

Original search

Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells