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As people keep their homes clean and clutter in check, a crew of cells within the body is in charge of clearing the waste that the body generates, including cells that are dying. The housekeeping cells remove unwanted material by a process called phagocytosis, which literally means’eating cells’
“Phagocytosis is quite important for the body’s health,” said Dr. Zheng Zhou, whose lab at Baylor College of Medicine has been studying phagocytosis for many years and provided key new insights into this essential procedure.
“When this cell-eat-cell process fails, the dying cells will lose their integrity, break down and release their content into the surrounding tissues. Dumping the cell content could cause direct tissue damage and activate inflammatory and autoimmune responses. If the dying cells are infected by a virus, releasing the mobile content would spread the infection.”
In the current study, Zhou, professor at the Verna and Marrs McLean Department of Biochemistry and Molecular Biology at Baylor, and her colleagues focused on necrosis, the type of cell death caused by injury or disease. Necrosis is mostly related to stroke, cancer, neurodegenerative diseases and heart conditions.
The team investigated in more detail the sign necrotic cells display which cues the’eating’ or phagocytic cells to engulf and eliminate the dying cell.
“In previous work, the Zhou laboratory showed that the signal in necrotic cells is phosphatidylserine, which is a kind of lipid,” said Yoshitaka Furuta, first author of the current study on which he worked while he was an undergraduate student intern at the Zhou laboratory. Furuta now is a student in Baylor’s Development, Disease Models and Therapeutics Graduate Program.
The team discovered that necrotic cells, but not living cells, expose phosphatidylserine on their outer surfaces and if phagocytes detect it, they ingest and destroy the cells that were dying.”
Healthy cells maintain phosphatidylserine in their inside, but when they’re injured, for example by lack of oxygen during a stroke when neurons are over excited due to constant entry of calcium ions, or during neurodegeneration, a process begins that ultimately flips phosphatidylserine to the outside of the cell. “We wanted to know what activates the flipping of phosphatidylserine,” Furuta said.
Following the process of necrosis in the transparent worm C. elegans
The researchers worked with the model organism C. elegans, a pig that is as long as a charge card is thick. C. elegans is transparent, allowing the researchers to visually identify necrotic neurons, which seem swelled when compared to living cells, and follow changes in the dynamics of cellular components with a time-lapse recording strategy they developed.
Previous work in C. elegans neurons had revealed that specific mutations in ion channel proteins, which regulate the flow of ions like calcium2+ in and outside of the cell, induced necrosis which was accompanied by an increase of calcium ion levels within the cell.
To investigate whether changes in calcium ion levels were linked to the triggering of this eat-me signal, the group introduced some of the ion channel mutant genes in neurons of the C. elegans version and monitored both calcium levels and phosphatidylserine over time.
We discovered in our model of necrosis that a robust and transient increase in calcium ions inside the cell preceded phosphatidylserine exposure in necrotic neurons.”
Dr. Zheng Zhou, Member, Baylor’s Dan L Duncan Comprehensive Cancer Center
“Further experiments showed that necrotic neurons first had a small increase of calcium ions, which prompted the release of calcium ions from an intracellular structure called the endoplasmic reticulum (ER), a larger source of calcium. Having bigger than normal calcium levels inside the cell triggered phosphatidylserine exposure.”
Supporting the role of calcium ions as a trigger of this’eat-cell’ signal, the researchers found that artificially increasing the level of calcium ions inside living cells also resulted in phosphatidylserine exposure and that limiting calcium release from the ER prevented exposure of the signal.
The team also zoomed in into the process leading to the turning of phosphatidylserine and found another piece of the puzzle. They discovered that a calcium increase inside the cells triggers ANOH-1, an enzyme known to promote phosphatidylserine exposure.
“It was intriguing to me that calcium can be good and bad for living cells,” Furuta said. “Too much calcium is toxic to cells and induces necrosis, but at exactly the same time calcium is necessary for dying cells to expose phosphatidylserine, the eat-me sign that boosts their clearance.”
“Necrosis is a universal phenomenon that’s present in various kinds of ailments and the clearance of necrotic cells is very important for keeping our bodies healthy,” Zhou said.
Our findings provide new insight into the process of necrosis which could potentially lead to the development of therapeutic strategies, possibly along the lines of encouraging clearance of necrotic cells by modulating phosphatidylserine exposure, which might lower the hazardous effects of necrosis and enhance cellular housekeeping.”
Baylor College of Medicine
Furuta, Y., et al. (2021) Calcium ions trigger the exposure of phosphatidylserine on the surface of necrotic cells. PLOS Genetics. doi.org/10.1371/journal.pgen.1009066.