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New insights in cell biology
LA JOLLA, Calif.—Salk Institute scientists have been busy delving into various mechanisms present in complex cell biology, with promising discoveries that may shed more light into the role of specific cells or cell behaviors that may contribute to cancer. In exploring mitosis at the granular level, they made a discovery that will help the field better understand how cells maintain their pre-division identity once two cells emerge. In addition, a deeper exploration of tuft cells in pancreatitis indicates a surprising role in immune functions.
“We wanted to understand the molecular mechanisms of cell identity and transcriptional memory,” says Hyeseon Kang, a UC San Diego graduate student in the Salk lab. “How does the mother cell pass on identity to the daughter cells through cell division?”
Cell division, also known as mitosis, is one of most basic—and most important—events in the function of the human body. Each cell must make a complete copy of its DNA and then split in two, with each subsequent cell holding the complete profile. In order to do this effectively, genes cease producing proteins just before the division occurs, restarting protein production once the two new cells are created. Cancer capitalizes on this brief absence of cell identity by using the opportunity to create DNA mutations, or future snags in the mitosis process. Scientists have known that this restarting of proteins is key to cells “remembering” their role in the body, but exactly how has been a mystery.
In the laboratory, cells are all in different stages of mitosis as they mingle within a cell culture, making it difficult to isolate any specific moment in an individual cell’s return to protein production and cell identity. With the help of a chemical inhibitor, Prof. Martin Hetzer and his team at the Salk Institute successfully calibrated retinal cells and bone cancer cells to align them at the same stage of the cell life cycle. This synchronization allowed them to scrutinize the moment when genes reactivate after dividing.
The team found that gene activation happens in a continuum, initiating immediately after division and progressing to other genes, a process that nudges cells to return to their root cell identity.
“We gained new insights into the memory mechanisms that allow the right genes to turn on at the right time, so that a new cell can become the same type of cell as the parent cell,” explained Hetzer, the paper’s senior author, holder of the Jesse and Caryl Philips Foundation Chair, and Salk’s chief science officer. “Our findings lay the foundation for understanding this brief and dynamic cell life stage that is critical for cellular identity.”
In a different Salk lab led by Prof. Geoffrey Wahl and staff scientist Kathleen DelGiorno, researchers have taken a deeper look at little-understood tuft cells—cells that are highly reactive to chemical changes found in the respiratory and intestinal tracts. Using mouse models of pancreatitis, they found tuft cell formation in pancreatitis while identifying a novel reason those cells are present.
“By understanding these early stages of pancreas disease, we hope our work will lead to the development of new strategies to diagnose and treat pancreatitis and pancreatic cancer early on,” commented Wahl, co-corresponding author and holder of the Daniel and Martina Lewis Chair in Salk’s Gene Expression Laboratory.
The pancreas consists of many acinar cells, which produce and secret digestive enzymes. While tuft cells are not normally found in the pancreas, acinar cells are capable of changing into intestinal tuft cells which secrete the protein IL-25 to support immune function, thus turning a preventive cell into a defensive one.
“Since cancer has been called ‘the wound that never heals,’ we wanted to investigate how the pancreas heals from pancreatitis to better understand pathways that may be co-opted by cancer,” Razia Naeem, co-first author and a laboratory technician in the Wahl lab, said in a press release.
The team explored pancreatitis samples from seven different strains of mice and found that the production of tuft cells did not occur in all strains of mice. In fact, it was the most genetically diverse mice that produced the most tuft cells, suggesting that tuft cell development may be either controlled genetically or influenced by gene expression. This suggests that genetically diverse mice may provide a better window into the complexity of human biology, allowing for a broader exploration of disease in the lab. It may also indicate that some people may be more susceptible to pancreatitis or other diseases than others.
“The genetic susceptibility of tuft cell formation may represent a critical factor in pancreatitis formation, severity and progression to cancer in humans,” remarked DelGiorno, first and co-corresponding author of the paper and staff scientist in the Wahl lab. “Our work demonstrates that it’s important to use the right mouse model to study pancreatitis and pancreatic cancer for there to be relevance to humans.”