Scientists build new techniques to reveal cell-cell interactions

A few months after the paper was submitted, it was called back by the reviewers, and a sharply worded review followed. But Huan Zhao, co-first author of the paper and an associate researcher at the Center for Excellence in Molecular Cell Science (Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, is not discouraged.

“In fact, as soon as the paper was submitted, Professor Zhou Bin (a researcher at the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences) realized the problem, and we have begun to improve this work.” Zhao Huan said.

However, they did not expect that this improvement would be another 3 years of hard work.


Photo courtesy of Zhou Bin

On December 2, the paper was published in Science, a top international academic journal. The team has developed an innovative research tool that captures cell-to-cell interactions in vivo and can permanently track neighboring cells – proximity cytogenetics.

This technology has been evaluated by peers as “relying on the sky sword”, and is expected to provide a powerful tool for the research of developmental biology, oncology and many other fields.

In life, how do cells “interact” with each other?

Cell-to-cell interactions are critical for biological growth and development and organ function maintenance. But these delicate processes take place in complex internal environments that are difficult for scientists to observe, let alone study.

In 2010, Zhou Bin returned to China after completing his postdoctoral research at Harvard Medical School, and came up with the idea of carrying out “neighboring cells” research.

Just like people, cells are significantly affected by “neighbors.” The same cells are in different environments, adjacent to different cell populations, morphological structure and physiological functions will show different characteristics, and even their fate will change depending on the environment.

This wonderful phenomenon fascinated Zhou Bin deeply. Over the past decade, he has guided students through a series of genetic tracing studies, during which he has made some progress, but those studies have used traditional genetic tracing techniques that can only be performed on the cells themselves. These studies obviously cannot satisfy the curiosity of researchers. Many years ago, the laboratory tried to study the genetic manipulation of neighboring cells in vivo. They set up an experimental system for this purpose, and carried out several optimizations.

“But the first three years basically failed.” Zhou Bin said, “It was not until later that we found a different way and began to try to introduce synthetic biology methods. Specifically, a completely new cellular pathway, Synthetic Notch (SynNotch), is synthesized to transform the contact between two neighboring cells in an organism into a genetic signal that can be studied. ”

Cell migration alters the .jpg cell interactions

Cell migration alters cell interactions Photo courtesy of interviewee

Ten years of grinding the “sword of heaven”

Since Zhou Bin has been engaged in research related to heart development for a long time and has a good understanding of the cardiovascular system, the team decided to use this as an entry point to carry out research. They took cardiac central myocytes and endothelial cells as the main research objects, cardiomyocytes as SynNotch signaling cells, and endothelial cells as SynNotch signaling cells, and constructed related tool mice respectively.

This is a very elaborate experimental design. When cardiomyocytes and endothelial cells come into contact or separate, different genetic signal manifestations are produced, reflecting real-time contact information between cells.

In 2018, Zhang Shaohua, a postdoctoral fellow in the team (co-first author of this paper), used experiments to preliminarily verify the feasibility of genetic manipulation of neighboring cells in vivo. This major breakthrough made everyone “excited” for a while.

Next, they further refined the system, enabling permanent tracer marking.

Through this technique, they discovered many interesting life phenomena: cardiac endothelial cells migrate to the liver during embryonic development and transform into liver-specific hepatic sinus endothelial cells, which may play an important role in maintaining the normal function of the liver.

During tumorigenesis, tumor vascular endothelial cells migrate to the tumor envelope. This part of the vascular endothelial cells that migrate to the tumor envelope still have typical characteristics such as metastasis and infiltration, pro-angiogenesis, and inflammatory response, indicating that the influence of the original environment on the cell may still exist after the cell enters the new environment.

“These results illustrate the amazing interaction of cells in the body.” Zhou Bin said, “This also suggests that cell-cell interactions have great application prospects.” For example, a cell is modified and then implanted in the body to affect the surrounding cells, so as to achieve the goal of genetic modification or disease treatment. For example, understanding the interaction between tumor cells and other organ cells during metastasis makes it possible to develop interventions to block cancer metastasis. ”

It is said that “ten years sharpen a sword”. In the view of Liu Xiaolong, director of the Center of Excellence for Molecular Cells of the Chinese Academy of Sciences, Zhou Bin has sharpened a “sword relying on the sky” and is expected to solve more complex life science problems in the future.

Li Lin, an academician of the Chinese Academy of Sciences, said: “Many important scientific discoveries often benefit from the innovation of key technologies. The tool mouse developed by Zhou Bin’s team is very worth looking forward to the ‘real-time, quantitative, dynamic and in situ’ description of life phenomena. ”


The study was published in Science Photo courtesy of interviewee

3 years of “supplement” handed over perfect answers

But such a surprising job, the submission process did not go smoothly.

In 2020, the team submitted a paper to Science for the first time. A few months later, the manuscript was returned, and one of the reviewers offered a “sharp opinion”, bluntly saying that “I am not optimistic about this ‘tool’ because the scope of application is too narrow, it is only an experiment on cardiovascular disease, and there are very few people who can actually use the technology”.

Everyone is not surprised by such feedback. They also hope that the system they have developed can be applied to more organs and tissues and play a more powerful role.

“At first, we didn’t think it would be too difficult to supplement the experiment and modify the system.” Zhao Huan said, “But the truth is not the same as we imagined. ”

In different biological tissues, different gene expression levels are different, and the strength of ligands and receptors is also different, which means that the upgrade of the system is by no means a simple “patch” and changing conditions, and many times it is even necessary to abandon some previously established systems and start all over again.

To this end, they further expanded the scope of teamwork, and cooperated with Professor Rong A. Wang of the University of California, San Francisco, researcher He Lingjuan of Westlake University and others, and finally built a system with wide applicability after 3 years of polishing.

In mice, this system can label any type of cell and use the cell to make all types of surrounding cells respond.

“The amount of work going on in this article is amazing. I am satisfied with the author’s revision data. “The hard work paid off, and the 3-year manuscript work was highly recognized by the paper reviewers. The reviewers believe that the authors have done a lot of experimental work, demonstrating the reliability of the technique and its application to many fields of biology.

Yang Xiao, a researcher at the National Center for Protein Science, who was not involved in this study, is also interested in the wide applicability of this result: “It provides an important technical means for in-depth exploration of cell fate plasticity in vivo, and is expected to be applied to study the influence of microenvironment cells on stem cells, immune cell interactions, neuronal contact, the effects of cancer cells and their relationship with neighboring immune cells, and also provide new strategies for disease treatment.” (Source: China Science News, Zhang Shuanghu, Li Chenyang, Huang Xin)

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