Cells they are a-changin'

Mature cells may be more plastic than we thought

In February, the Boston Globe health section ran a top-of-the-fold story about Harvard Stem Cell science. With input from three HSCI faculty members, the article described how, in the process of developing the field of regenerative medicine, basic stem cell researchers have rewritten some of the underlying principals of biology.

“It’s slowly changing how we think about life, and I know that sounds grandiose, but it’s not grandiose at all,” explained Brigham and Women’s cardiologist Richard Lee, MD. “We’re starting to get a better handle that cells maybe can do things that we never thought they could do.”

One such example can be seen in a series of recent papers on cell plasticity, the ability of one type of cell to become another type of cell. It has long been believed that the main difference between a stem cell, or progenitor cell, and a mature or adult cell is that the latter are not plastic. But new research shows that in some organs—including the adrenal glands, kidneys, and lungs—mature cells can change identity. Scientists think this information could lead to new therapeutic strategies.

Last September, HSCI Principal Faculty member David Breault, MD, PhD, showed that the outer cells of the adrenal glands, which sit atop the kidneys, give rise to the inner cells of the adrenal gland through a process of cellular reprogramming (called lineage conversion). The transformation happens both during daily maintenance and following injury.

“As early as the 19th century it was known that the adrenal gland could undergo regeneration,” said Breault, an endocrinologist at Boston Children’s Hospital. “Despite this, the rules that control that regeneration are not well understood.”

His lab began to focus on how known hormones are able to switch adrenal regeneration on and off. They discovered a gene, steroidogenic factor 1, which is responsible for establishing the adrenals, ovaries, and testes during development. When Breault’s team turned off this gene in the adult adrenal, they saw that it stopped the cellular reprogramming.

“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,” he said.

Breault believes that better understanding of the gland’s biology and regeneration will pave the way for cell or gene-based therapies of adrenal diseases in the future.

A few weeks after Breault announced his discovery, HSCI Kidney Program Leader Benjamin Humphreys, MD, PhD, described similar plasticity in kidneys.

He found that after injury, mature kidney cells dedifferentiate into more primordial versions of themselves, and then differentiate into the cell types needing replacement in the damaged tissue. This finding conflicted with a previously held theory that the kidney has scattered stem cell populations that respond to injury.

“Not every organ necessarily is endowed with clear and well-defined stem cell populations, like the intestines or the skin,” said Humphreys, who is located at Brigham and Women’s Hospital.

“I’m not saying that kidney stem cells don’t exist,” he added, “but in tissues where cell division is very slow, there may not have been an evolutionary pressure for stem cell mechanisms of repair.”

Then, in November, Jayaraj Rajagopal, MD, at Massachusetts General Hospital, published another example of mature cell plasticity, this time in the lung. He provided the first evidence that the cells that line the airways can revert back, or dedifferentiate, into stem cells as a way to heal damaged tissue.

“The dedifferentiated cells function as well as their normal stem cell counterparts in repairing injury,” he said. “The capacity of committed cells to dedifferentiate into stem cells may have a more general role in the regeneration of many tissues and in multiple disease states.”

Rajagopal suspects that the findings have implications for cancer biology, as this natural cell plasticity in the lung could be used to enhance tumor growth. There are
still more surprises to come.