“Who would have thought that an accidental discovery would overturn a century-old conclusion in immunology?” said Zhisheng Wu, speaking of his research findings with delight.

On the evening of April 7, Zhisheng Wu from the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, under the guidance of his supervisor Hanjie Li, published his research findings as the first author on the international academic journal Cell. This study confirmed the existence of microglia in the human peripheral nervous system for the first time, offering a new viewpoint and potential targets for exploring system development and related diseases.

“Unexpected” discovery rewrote traditional understanding

In 2021, Hanjie Li returned to China and joined the Shenzhen Institute of Advanced Technology to build a team. At that time, Zhisheng Wu, a first-year Ph.D. student at Southeast University, came to Li’s team for a four-year project internship due to his school supervisor’s recommendation.

In the same year, Li’s team accidentally detected genetic characteristics of microglia in single-cell sequencing data of peripheral tissues like skin, heart and testes, while constructing a human embryonic immune cell development map.

After repeated verification, the team demonstrated the presence of numerous microglia in these peripheral tissues. In September 2023, they published this finding in Cell, drawing wide academic attention.

However, the team didn’t stop here. They subtly realized that if microglia could be in peripheral organs, they might also be in the peripheral nervous system. Based on this assumption, they began over a year of “free exploration”.

Groping in the dark, and opening the door to truth

“The process of proving the existence of microglia in the peripheral nervous system was like grope in the dark, challenging at every step, before the door to truth slowly opened,” recalled Zhisheng Wu.

To test their hypothesis, the team first analyzed human embryo samples at different development stages, and found a surge in microglia in the peripheral nervous system as the embryo develops.

Next, in collaboration with the First Affiliated Hospital of Sun Yat-sen University, they obtained adult dorsal root ganglia samples and identified a cell group in the adult peripheral nervous system highly similar to microglia in the central system. Epigenetic and developmental biological analyses confirmed these cells belong to the microglial lineage.

To investigate the evolutionary conservation of this phenomenon, the team conducted a cross-species comparison study on 24 vertebrates. Results showed that microglia in the peripheral nervous system emerged at least 430 million years ago in the ancestor of bony fish.

Seeking science, and exploring the unknown

“For free exploratory research, we never know what new discoveries will be made in the next second. This process requires the courage to question science and explore the unknown.” This is the second top journal article of Zhisheng Wu during his Ph.D. He believes that besides luck, solid skills and a strong team platform are crucial.

Set to graduate this year, Wu plans to pursue a postdoctoral fellowship with Li’s group to continue deeply studying microglia in the peripheral nervous system. Speaking of the future, he said, “Research is a long journey. With curiosity, breakthroughs are sure to come.”