HomeScienceGeneticsResearchers make organoids of the adrenal gland using stem cells

Researchers make organoids of the adrenal gland using stem cells

A team coaxed stem cells to take on the characteristics and functions of a human adrenal gland, advances that could lead to new therapies for adrenal insufficiency and a better understanding of the genetics of such conditions. People with adrenal disorders, such as primary adrenal insufficiency, where the gland doesn’t release 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, regrowing a functional adrenal gland capable of synthesizing hormones and releasing them appropriately in accordance with feedback from the brain. With a new study in the journal Developmental Cell, researchers at the University of Pennsylvania School of Veterinary Medicine coaxed stem cells in a petri dish to divide, mature and take over some of the functions of a human fetal adrenal gland, achieving that goal. is reached. step closer. “This is a proof-of-principle that we can create a system grown in a dish that functions almost identically to a human adrenal gland in the early stages of development,” said 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 for drug screening to identify better therapies for people with these conditions.”

Sasaki says his team’s goal was to use human inducible pluripotent stem cells (iPSCs), which can give rise to a wide variety of cell types, to mimic the stages of normal human adrenal development. During this process, the cells would be instructed to take on the characteristics of the adrenal gland. To begin with, the researchers used a system known as an “organoid culture” system, in which cells first grow as a floating aggregate for three weeks, then on a membrane exposed to air on one side, which improves their survival and multiply in threes. dimensions. Using a carefully selected growth medium, they prompted the iPSCs to induce an intermediate tissue type in the adrenal developmental process, the posterior intermediate mesoderm (PIM).

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After verifying they had grown PIM-like cells, the researchers began guiding those cells into the transition to the next stage, adrenocortical progenitor-like cells, in which cells turn on markers that indicate they are “committed” to become adrenal cells. . Molecular tests to check for adrenal markers, as well as transmission electron microscope analyses, all told Sasaki and colleagues they were on the right track to creating a tissue that resembled the early adrenal gland.

“The process we developed was very efficient, with about 50% of the cells in organoids given the fate of the adrenocortical cells,” said Michinori Mayama, a postdoctoral fellow in Sasaki’s lab and a lead author on 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 that stage.” Sasaki, Mayama and the rest of the research team performed a number of tests to evaluate how closely the functionality of the cells they cultured mirrored that of a human adrenal gland. They found that the lab-grown cells produced steroid hormones, such as DHEA, just as the “real” equivalent would. “In vitro we can produce many of the same steroids that are produced in vivo,” says Mayama.

They also showed that the cells they cultured could respond to what’s known as the hypothalamic-pituitary-adrenal axis, a feedback loop that controls communication from the brain to the adrenal gland and back again. “We used drugs that normally suppress DHEA production in the adrenal gland and showed that our iPSC-derived adrenal cells respond similarly to these drugs, with a marked reduction in hormone production,” says Sasaki. “This means you can use this system to screen drugs that target adrenal hormone production, which could be beneficial for patients with excess adrenal hormone production or with prostate cancer that uses adrenal hormones for their growth.” As the researchers refine their system, they hope to be able to generate more of the gradations in tissue type that occur in a mature adult adrenal gland.

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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 investigate the genetic basis of adrenal insufficiency and other diseases, such as adrenal carcinomas. Ultimately, the approach used to create this gland-in-a-shell may one day work to reconstruct a functioning brain-adrenal feedback loop in people with adrenal disorders. “This is a first study of its kind,” says Sasaki. “The field of cell therapy holds so much promise for the treatment of not only adrenal insufficiency, but other hormone-induced diseases: hypertension, Cushing’s syndrome, polycystic ovary syndrome and more.”

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(This story has not been edited by Devdiscourse staff and is automatically generated from a syndicated feed.)

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