Adrenal gland offers a new view of tissue regeneration and maintenance

A confocal micrograph of a mouse adrenal gland. The green stripes radiating from the outer region containing the zona glomerulosa (zG) to the inner region containing the zona fasiculata (zF) provide evidence for direct lineage conversion of these two differentiated cell types.
In this mouse adrenal gland, the green stripes radiating from the outer region containing the zona glomerulosa (zG) to the inner region containing the zona fasiculata (zF) provide evidence for direct lineage conversion of these two cell types.

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 ever occurs in nature. In fact, it does, discovered David Breault, MD, PhD, an endocrinologist at Boston Children’s Hospital and a member of the Harvard Stem Cell Institute. In the journal Developmental Cell, Breault recently showed that the adrenal gland uses cellular reprogramming (called lineage conversion) for daily maintenance and to repair itself after injury.

“This is going to be important for how we think of tissue maintenance and regeneration,” Breault says.

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, the 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 19th century—known to undergo regeneration,” says Breault. “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 such as ACTH are able to switch adrenal regeneration on and off. The investigation led to a gene called steroidogenic factor 1, which is responsible for establishing the adrenals, ovaries and testes during early development. When Breault’s team turned off this gene in the adult adrenal gland, 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 hypoplasia, and 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 disorders in the future.

“Usually, once a cell becomes completely mature, it keeps its identity until it dies, but this is an exception—one of the few cases where one completely mature cell decides to go and turn into another completely mature cell,” says study co-author Joseph Majzoub, MD, chief of endocrinology at Boston Children’s. “The findings also provide the answer to a longstanding puzzle about how the adrenal gland develops—the answer is essentially from the outside-in.”

The biology of the adrenal gland also 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, possibly through a similar cellular reprogramming operation.

Joseph Caputo is communications manager at the Harvard Stem Cell Institute.

Source: Freedman BD; et al. Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Developmental Cell 2013 Sep 30; 26:666-73. doi: 10.1016/j.devcel.2013.07.016.