The incredible process of cell division can transform a fertilized egg into a baby or a cancerous cell into a malignant tumor. With so much on the line, nature tightly controls this process through the cell cycle, which scientists believed they fully understood. UCSF scientists have now discovered that multiciliated cells adapt the well-known process of cell division to produce hundreds of cilia.The cell cycle was believed to be well understood by scientists, but now they have discovered that there is more to learn. Researchers at UC San Francisco have found that cells can use the cell cycle to regulate the growth of hair-like projections known as cilia. According to Jeremy Reiter, a UCSF professor, and senior author of the paper published in Nature on May 29, 2024, “The cell cycle has been extensively studied for decades, and here, we’ve discovered a new way in which it operates. This old concept – the cell cycle – has more capabilities than we previously thought.”
Taking measures to prevent cancer is essential
Cells with multiple cilia play a crucial role in maintaining human health. They are responsible for keeping fluids like mucus from accumulating in the lungs by swaying back and forth. In the reproductive system, they aid in the movement of eggs through the fallopian tubes and into the uterus. In the brain, they help remove waste by sweeping out cerebrospinal fluid. When these cells do not function properly, it can lead to serious diseases.
Reiter and his team aimed to comprehend the development of these cells. They utilized a method called single cell RNA sequencing to observe the activation and deactivation of genes in individual multiciliated cells in the lungs.
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They caught the cells at different points in their development in the hope of uncovering the genetic instructions needed to grow cilia. What they found resembled the cell cycle.
Prior research discovered that a small number of cell cycle proteins, known as cyclins, were active during cilia growth. Additionally, centrioles, which hold the two sets of chromosomes in place during cell division, were also involved.
However, Reiter’s team observed that many cell cycle genes, not just cyclins, were highly expressed in the lung cells, even though the cells were not dividing.
“As the multiciliated cells developed, we noticed the same sequential expression of Cell cycle regulators, such as cyclins and CDKs, that we would expect to find in stem cells,” said Semil Choksi, PhD, a researcher in the Reiter lab and the primary author of the paper. This was not the typical cell cycle. For one, this alternate cell cycle, or “multiciliation cycle,” as the scientists called it, was producing an unusually high number of centrioles, much more than the four centrioles created during cell division. “If something goes wrong in the cell cycle and you create too many centrioles, it can lead to cancer,” Choksi said. “Somehow, this strict rule preventing cancer, no more than four centrioles per cell, The process of multiciliation is very specific in cells with multiple cilia, leading to the formation of hundreds of centrioles.”
A new composition in cellular activity
Choksi and Reiter conducted a thorough investigation into the differences between the multiciliation cycle in lung cells and the typical cell cycle in dividing stem cells, focusing on individual genes. One gene, known as E2F7, was particularly noteworthy. Its level of expression was moderate in stem cells, but significantly elevated in maturing multiciliated cells.
When E2F7 was completely disabled, or knocked out, in an animal model, multiciliated cells failed to develop properly, resulting in issues in the b
The researchers believed that increasing E2F7 could potentially shift the standard cell cycle to the multiciliation cycle,” Reiter explained. Afterward, they observed that multiciliated cells without E2F7 began producing new DNA, indicating cell division. Additionally, numerous centrioles were trapped inside the cell body, preventing the eventual formation of cilia on the cell surface.
If the cell cycle were compared to a musical score, E2F7 acted as a conductor guiding the molecular orchestra to play a new tune, the multiciliation cycle.
“The cell cycle has been adapted by evolution to perform various tasks beyond just cell division,” said Reiter. “It will be interesting to discover its other capabilities.”
