In 2006, Shinya Yamanaka, MD, PhD, discovered a way to reprogram mature skin cells back to a stem cell state so they can be converted into any cell type a scientist is interested in studying. That work earned him last year’s Nobel Prize in Physiology or Medicine.
Yamanaka’s discovery raised the tantalizing question of whether similar reprogramming occurs in nature. In fact, it does, discovered HSCI Principal Faculty member David Breault, MD, PhD, who has just shown that the adrenal gland uses cellular reprogramming (called lineage conversion) for both its daily maintenance and regeneration following injury.
The triangle-shaped adrenal glands sit atop the kidneys and release stress hormones to help the body respond to challenges in the environment. To ensure that just the right amount of stress hormone is produced each day, cells of the adrenal are continuously renewed throughout a person’s lifetime. If this system fails, too much stress hormone may be produced, which can lead to heart disease, digestive conditions, poor memory, and other problems.
“The adrenal gland was one of the first tissues—as early as the nineteenth century—known to undergo regeneration,” said Breault, an endocrinologist at Boston Children’s Hospital. “Despite this, the rules that control its regeneration following injury or its daily maintenance are not well understood.”
His lab began to focus on how known hormones (e.g., ACTH) are able to switch adrenal regeneration on and off. The investigation led to a gene called steroidogenic factor 1, which during development is responsible for establishing the adrenals, ovaries, and testes. When Breault’s team turned off this gene in the adult adrenal, they saw that it stopped the cellular reprogramming.
“It completely blocks the ability of one of these cell types—the outer adrenal cell type—to give rise to the inner adrenal cell type,” he said. “So the process of lineage conversion is dependent on this gene, which means it plays an entirely different role in adults than it does in development.”
Adrenal gland dysfunction is associated with severe illnesses such as Addison’s disease and congenital adrenal hyperplasia, and under activity commonly results from prolonged treatment with steroids such as prednisone. Breault believes that better understanding of the biology of the gland, and its regeneration, will pave the way for cell or gene-based therapies for these diseases in the future.
In addition, the biology of the adrenal gland could provide clues to how other tissues are maintained and respond to stress. In the pancreas, for example, it’s been suggested that glucagon-producing alpha cells may be able to give rise to insulin-producing beta cells, which could possibly operate through a similar means of cellular reprogramming.
An HSCI Junior Faculty Program grant, the Timothy Murphy Fund, and the National Institutes of Health funded this research.
Research cited: Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Developmental Cell. Sept 12, 2013