New insights discovered on the mechanism of cell plasticity through research

Researchers have long believed that once a cell has embarked on a differentiation pathway, growing into a skin cell, liver cell, or nerve cell, that pathway cannot be altered.

But over the past two decades, scientists have realized that this pathway is much more complex. Now, using zebrafish as a model, a research team at the University of Michigan has discovered that a loop in the body’s mitochondria — the intracellular organelles that produce energy for the body — may allow cells to fall back on their path of differentiation. Their results are published in Proceedings of the National Academy of Sciences.

“The fate and differentiation of a cell is similar to a ball going down a hill. The ball is the stem cell. The stem cell divides and becomes a progenitor cell, which will become the future skin, nerve cell, liver, and muscle cell. This ball is just that,” said Kunming Duan, professor of molecular, cellular and developmental biology. and director of the undergraduate program in Neuroscience, “I ran the idea off a cliff for a long time.”

“People also think this applies to adult tissue regeneration. If you cut your skin or injured a muscle, the idea was that there was a pool of adult stem cells doing the same thing: It was a ball rolling down a hill. But beginning in the last few decades, researchers have shown that this is excessive.” In simplification”.

Duane says researchers now understand that a cell can cross the hill and become a different type of cell and that cells can come back up the hill and become a precursor cell to make more cells. For example, in the human pancreas, cells called alpha cells produce a hormone called glucagon. The beta cells of the pancreas produce the hormone insulin. But alpha cells can become beta cells.

Cells can also not differentiate if they are stressed or injured. For example, if a beta cell can dedifferentiate, it becomes a progenitor cell and produces more healthy beta cells.

Recent studies have shown that dedifferentiation isn’t actually unique: Many fully differentiated cells can roll up a hill if they injure tissue, Duan says. Cancer cells also exhibit this type of plasticity, which complicates the ability to treat them.

Duan said previous studies to understand the dedifferentiation process were conducted in artificial systems. You cannot surgically remove a portion of a fish’s heart or cut out a portion of a mammal’s liver and study cellular processes. So Duan and his research team developed a model in zebrafish.

In the model, the researchers labeled the calcium ion transporter of epithelial cells with a green fluorescent protein that lights up these cells. Using that, they were able to induce these differentiated cells to re-enter the cell cycle and visualize cell division, zooming in particularly on the processes involving mitochondria.

Mitochondria are often called the “power centers” of the cell. They produce ATP, the energy-carrying molecule in the cells of all living things. Mitochondria do much more than that, Duane said. When they break down sugar to produce ATP, they also produce what are called reactive oxygen species, or ROS, which are highly reactive chemicals that can cause cellular damage.

However, when mitochondria release ROS, in the right amounts, they act as signaling molecules. The team found that when cellular differentiation and proliferation were induced, ATP production increased and ROS levels rose in the mitochondria of these cells.

When ROS levels are elevated, an enzyme that plays a role in cellular stress response called Sgk1 is also increased in the cell cytoplasm. Next, Sgk1 translocates from the cytoplasm into the mitochondria, where it phosphorylates the enzyme that synthesizes ATP and catalyzes ATP production.

To test the effect of this loop on the cell’s ability to dedifferentiate, the researchers blocked every step in this cycle.

“We feel this is really required for the cell to go backwards in the cell cycle,” Duane said. “In our system, if we remove ATP, if we remove Sgk1, if we block ROS production — if we block any of the steps, the cell can’t get back up again in the cell cycle.”

The researchers then examined the mitochondrial loop in live human breast cancer cells and found that the same steps occurred in human breast cancer cells. This suggests that this is a commonly used mechanism that is beneficial to most cells, they say.

Cancer cells are just one of Duane’s cell types, and his team hopes the discovery will be targeted one day. Understanding cell plasticity is important in regenerative biology for tissue regeneration, but it is also important for diseases such as cancer.

“Cancer cells also have this kind of plasticity, and it’s considered one of the main challenges why we can’t easily treat cancer cells. If you eliminate one cancer stem cell, another can come back,” Duan said.

Next, Duane hopes to better understand this mitochondrial loop in other cell types, with the idea that the pathway could one day be targeted to regenerate tissues and prevent abnormal growths, such as cancer.

“Cells and animals are a lot more flexible than we used to think,” he said. “They’re a lot more plastic. We used to think they were kind of tough.” “Mitochondria play a much more important role in the cell than we ever thought they would play. We found a very complex pathway operating at the subcellular level that determines the cell’s ability to be flexible and to be plastic.”