"Sun Wukong" of the cell world, how to release it from under the "Five Elements Mountain"?

Produced by: Science Popularization China

Author: Wang Fei (PhD in Neuroscience)

Producer: China Science Expo

“72 changes” of stem cells

Recently, the domestic game "Black Myth: Wukong" has become very popular, not only because the domestic game industry has made great progress, but also because the image of the Monkey King Sun Wukong created by us is so classic. So I found the 1986 version of the classic "Journey to the West" and read it again. The image of Sun Wukong came alive again in my mind. Of course, today I want to talk not only about Sun Wukong, but also about a type of cell in our body that is very similar to him, which is stem cells.

Black Myth: Wukong game poster

(Image source: Black Myth: Wukong game official website)

Speaking of Sun Wukong, all children know that he has the ability to transform into 72 different forms, and stem cells can also transform into 72 different forms, or even more. Stem cells are a type of cell in our body with unlimited potential, which can become nerve cells, blood cells, muscle cells, bone cells and many other cells. Moreover, stem cells can change from one to two, from two to four... Thousands of cells are transformed from one stem cell. This reminds me that Sun Wukong can turn into many Sun Wukongs by pulling out a hair, isn't this learned from stem cells!

Another feature is that stem cells can continue to proliferate, and it can be said that they are "immortal", which is somewhat similar to Sun Wukong. It can be said that with stem cells, many diseases we encounter in life can be overcome. For example, if a patient has leukemia and does not have enough white blood cells, the stem cells can be turned into countless white blood cells. In the future, we will no longer see the painful ending of the protagonist dying of leukemia in TV dramas.

Functions of stem cells

(Image source: The National Academies)

We also have stem cells in our brains, called neural stem cells. However, the neural stem cells in the adult brain are more like Sun Wukong who is pressed under the Five Elements Mountain. He has all his abilities but cannot use them.

How to awaken dormant neural stem cells in the brain and unleash their unlimited potential to treat brain diseases is a major issue in modern scientific research and medical fields. Saving stem cells in the adult brain is not only of great significance, but also during human development, if neural stem cells cannot be unsealed and transformed into other cells on time, it will affect brain development and lead to neurodevelopmental disorders such as microcephaly, autism and cerebral palsy. Therefore, activating dormant neural stem cells and allowing them to produce new neurons is crucial for the repair and growth of the brain.

This reminds me that the most important episode in Journey to the West is when Tang Seng encountered Sun Wukong, who was trapped under the Five Elements Mountain. If he had not taken that path, or had not seen the monkey under the mountain, or had been scared away by it, there would not have been the 81 trials that followed, and the Tang Empire would not have welcomed the true teachings of the Mahayana Buddhism.

Stills from Journey to the West

(Photo source: CCTV)

Unlocking the "Five Elements Mountain"

So how do we unseal neural stem cells and release them from under the "Five Elements Mountain"? First, we need to know what the "Five Elements Mountain" is that holds neural stem cells back from performing magic.

Laboratories from Duke University and the National University of Singapore jointly studied the reasons for neural stem cell dormancy. Using ultramicroscopy and live cell imaging techniques, they found that there are some cytoskeletal proteins in dormant neural stem cells, called F-actin (chain actin). These filamentous cytoskeletal proteins keep moving during the process of neural stem cells changing from dormancy to activation. They gradually move from the protrusions of the cells to the cell body, and then gather in the cell body, and then the cell divides.

Stem Cells

(Photo source: veer photo gallery)

It can be said that it is these cytoskeleton that firmly controls the activation of neural stem cells. They are the "Five Elements Mountain" pressing on neural stem cells. Their movement is like the movement of the Five Elements Mountain when it collapses. Therefore, as long as the key to controlling the movement of F-actin is mastered, the dormant neural stem cells can be released.

Silencing F-actin in neural stem cells

(Image source: Lin et al., Sci. Adv. 10, eadl4694 (2024))

How to shake the Five Elements Mountain? In fact, the Five Elements Mountain is not heavy. Sun Wukong can overturn it with his own ability. The key lies in the seal on the Five Elements Mountain, which is the key to suppress the Five Elements Mountain. So for neural stem cells, what is the seal that controls the cytoskeleton F-actin?

The joint team found that a specific type of Formin protein (chain actin polymerase) controls the changes in the cytoskeleton F-actin, and thus controls the process of neural stem cell activation. In the laboratory, when they removed the Formin protein, the neural stem cells could not enter the activated state from the dormant state well. Of course, the cytoskeleton F-actin that bound the neural stem cells could not change.

Stills from Journey to the West

(Photo source: CCTV)

In Journey to the West, after Sun Wukong caused havoc in Heaven, he was imprisoned under the Five Elements Mountain by the Buddha for 500 years. He was finally rescued by Tang Sanzang, and together they traveled west to seek Buddhist scriptures, and finally achieved enlightenment. Who is "Tang Sanzang" in our brains? How does the "Tang Sanzang" in our brains remove the seal on the Five Elements Mountain and reactivate dormant neural stem cells?

The research team found that the astrocytes in the brain are the "master" who rescued "Wukong". Astrocytes are a subtype of glial cells in our brains, and they are named because of their irregular star-like shape. Their general function is to protect nerve cells and provide nutrition for them. Here, the researchers have discovered their new function, which is to activate neural stem cells.

The researchers observed that astrocytes secrete a protein called Fog (folded gastrulation protein), which acts as a signaling mediator and triggers a series of chain reactions, including the activation of the Formin protein pathway to control the movement of chain actin. Finally, these processes awaken neural stem cells from their dormant state, and then neural stem cells begin to divide and produce new nerve cells that contribute to brain repair and development.

Astrocytes

(Image source: ScienCell Research Laboratories)

Intracellular signaling “spells”

Through this process, we can see that astrocytes activating neural stem cells is not simply removing the "seal", but involves a complex signal transmission process. This is just like when Tang Monk lifted the seal on the Five Elements Mountain, he also knelt down and prayed, chanting a spell. Only through the correct spell can the seal be lifted.

Imagine if Tang Seng did not have enough knowledge of Buddhism and could not accurately recite the spell to unseal the Monkey King, he would not be able to rescue Sun Wukong. So what is the spell that astrocytes use to unseal dormant neural stem cells in our brain?

Stills from Journey to the West

(Photo source: CCTV)

Here, I will briefly introduce to you how astrocytes activate dormant neural stem cells. As mentioned above, astrocytes secrete Fog protein, and the receptor protein called GPCR in neural stem cells then responds to Fog secreted by astrocytes, activating the signaling pathway that controls the formation of chain actin in neural stem cells.

This pathway includes "signal messengers" such as Gαq, Rho1, and Dia. The instructions to release the seal will eventually act on the chain actin through these signal messengers, causing it to change its shape and release the dormant neural stem cells.

Signal messenger on the road

(Image source: Lin et al., Sci. Adv. 10, eadl4694 (2024))

It can be seen that the process of astrocytes in the brain activating dormant neural stem cells is complex. They activate the GPCR receptors on neural stem cells by secreting Fog protein, and the GPCR receptors in the cell bodies of neural stem cells open chain actin through the Gαq-Rho1-Dia signaling pathway, finally activating neural stem cells. This process can be filmed into the episode "Tang Monk Saves Wukong" in the TV series "Journey to the West"!

This seemingly simple process actually contains a lot of information. It was not easy for Yang Jie, the director of the 1986 version of Journey to the West, to film it, and it can also be said that the scientific researchers went through a lot of hardships to present this process in the body.

Astrocytes activate dormant neural stem cells

(Image source: Lin et al., Sci. Adv. 10, eadl4694 (2024))

After being rescued, Sun Wukong followed Tang Monk to slay demons and monsters, and finally retrieved the true scriptures after going through 81 trials. He was also named "Fighting Buddha". In the brain, activated neural stem cells are also extremely useful. Timely activated neural stem cells can become various types of nerve cells during brain development, greatly reducing the impairment of cognition, communication, adaptive behavior and psychomotor skills caused by neurodevelopmental disorders.

Conclusion

By studying this process, we have mastered the "mantra" to unlock neural stem cells and become "Tang Monk". When we need it, we can recite the mantra to activate neural stem cells. For example, we know that GPCR is a key step in the mantra, and the GPCR protein family has become a major drug target for the treatment of various diseases. If we design drugs targeting CPCR, we can control the reactivation of neural stem cells.

This idea provides a potential strategy for using existing drugs to treat neurodevelopmental disorders and also gives us a new way to activate neural stem cells.