Novel Mechanism of mRNA Transfer via Tunneling Nanotubes Discovered

Cell-to-cell communication is fundamental to all stages of life, and researchers have long studied its various mechanisms. In recent years, growing evidence has revealed that RNA—beyond its role in storing genetic information and regulating gene expression—also plays a part in intercellular communication.

One way messenger RNA (mRNA) is transmitted between cells is through extracellular vesicles. These small, membrane-bound structures carry biomolecules, including RNA, and are absorbed by neighboring cells. Another, less understood mode of RNA transfer occurs through direct contact, where tubular structures form between cells. However, limited studies have explored this mechanism, particularly in the context of stem cells, leaving its biological significance largely unknown.

To shed light on this process, a research team led by Professor Takanori Takebe at the Institute of Science Tokyo, Japan, investigated how mRNA is transferred between different types of stem cells and the functional implications of this transfer. Their findings were published on January 22, 2025, in Proceedings of the National Academy of Sciences (Vol. 122, Issue 4).

Using a coculture experiment, the researchers examined mRNA trafficking between human primed pluripotent stem cells (hPSCs) and mouse embryonic stem cells (mESCs). "When we started this coculture for a different purpose, we almost serendipitously found this unexpected mRNA transfer phenomenon, as we could distinguish endogenously expressed genes from laterally transferred mRNAs based on genetic sequence differences between mice and humans," said Professor Takebe.

By combining their experimental setup with RNA imaging and mouse-specific gene expression analysis, the team confirmed that mRNA from mESCs migrated into hPSCs. A detailed analysis revealed that these transferred mRNAs encoded molecules involved in transcription, translation, and stress response.

The researchers also identified the mechanism responsible for this transfer: tunneling nanotubes—thin, tunnel-like membrane extensions connecting cells—served as conduits for mRNA movement between mouse and human cells.

Next, the team investigated the biological effects of this transferred mRNA on the receiving cells. Surprisingly, they found that primed hPSCs reverted to a more "naïve" state, essentially returning to an earlier embryonic stage of development. This suggests that intercellular mRNA transfer can influence cell fate, extending beyond simple molecular exchange to actively shaping cellular identity. The researchers also identified key transcription factors involved in maintaining pluripotency.

Together, these findings highlight the critical role of mRNA transfer in intercellular communication. "This study provides insights into a novel mechanism of intercellular communication, illustrating how cell populations coordinate and interact with their environment," said Yosuke Yoneyama, the study's first author from the Institute of Integrated Research at the Institute of Science Tokyo. "We expect our findings to contribute to the development of new cell-fate control technologies that do not rely on artificial gene introduction or chemical compounds."

These discoveries could open new avenues for regenerative medicine, potentially leading to innovative therapies and drug development. While much remains to be explored, Takebe’s team is eager to continue unraveling the complexities of cell-to-cell communication and its broader implications for biology and medicine.