In a study published November 21 in the journal Developmental Cell, the researchers contend that their work could potentially lead to new therapies for adrenal insufficiencies and a better understanding of the genetics of the disorders.

"The mechanisms leading to adrenal cortex development and steroid synthesis in humans remain poorly understood due to the paucity of model systems," the study's authors write. "These findings provide a framework for understanding and reconstituting human adrenocortical development in vitro, paving the way for cell-based therapies of adrenal insufficiency."

Leveraging human inducible pluripotent stem cells (iPSCs) with the ability to create different cell types, the research team set out to mimic the stages of normal human adrenal development by directing the iPSCs to take on the characteristics and functionality of the adrenal gland.

In the lab, the researchers were able to prompt the iPSCs to elicit an intermediate tissue type in the adrenal development process -- the posterior intermediate mesoderm (PIM). Following verification that they had cultured PIM-like cells, they caused the cells to transition to the next phase -- adrenocortical progenitor-like cells -- in which cells turn on markers indicating they have "committed" to becoming adrenal gland cells.

Using molecular assays to check for adrenal markers and transmission electron microscope analyses, the team confirmed they had recreated a tissue resembling an early adrenal gland, with approximately 50% of cells in organoids "acquiring adrenocortical cell fate." Not only did researchers find that the lab-grown cells produced steroid hormones, such as dehydroepiandrosterone (DHEA), but they also demonstrated that the cells could respond to the hypothalamic-pituitary-adrenal axis, a feedback loop that governs two-way communication between the brain and the adrenal gland.

"We used drugs that normally suppress adrenal DHEA production and showed that our iPSC-derived adrenal cells respond similarly to these drugs, with a marked reduction of hormone production," senior author Dr. Kotaro Sasaki, PhD, an assistant professor at Penn Vet, said in a statement. "This means that you can use this system for screening drugs that target adrenal hormone production, which could benefit patients with excessive adrenal hormone production or with a prostate cancer that exploits adrenal hormones for their growth."

Going forward, Sasaki contends that his team's work could lead to better understanding of the genetic basis of adrenal insufficiencies as well as other diseases, such as adrenal carcinomas. In addition, he believes their approach to creating the organoid may help to recreate a functioning brain-adrenal gland feedback loop in patients with adrenal gland disorders.

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