Cell Connects: Breaking Barriers in Stem Cell Communication Through mRNA Transfer

Messenger RNA can travel between different types of stem cells through tunnel-like structures, as revealed by a new study. By studying interactions between mouse and human stem cells, they discovered that this RNA transfer can reprogram human cells to an earlier developmental state. This groundbreaking finding not only sheds light on an underexplored form of cellular communication but also suggests promising applications in regenerative medicine without using artificial genetic modifications or external chemicals.

Cell-to-cell communication is essential throughout all forms and stages of life, and many communication mechanisms are well studied. However, over the past few years, scientists have found increasing evidence that RNA, which carries genetic information and regulates gene expression, is also involved in intercellular communication.

One way in which messenger RNA (mRNA) transmission happens is through extracellular vesicles. Cells secrete small-sized, membranous vesicles containing biomolecules, including RNA, and these are taken up by nearby cells. A less understood mechanism of mRNA transfer involves tubular structures that form when cells come into contact. However, very few reports on this type of mRNA movement have been made, and the biological significance of this type of communication in stem cells remains mostly a mystery.

Against this backdrop, a research team led by Professor Takanori Takebe from Institute of Science Tokyo, Japan, investigated the mechanisms and roles of mRNA transfer between different types of stem cells. Their findings were published in the journal Proceedings of the National Academy of Sciences on January 22, 2025, in Volume 122, Issue 4.

To more easily detect mRNA trafficking from one cell to another, the researchers employed a coculture experimental system. Simply put, they cultured mouse embryonic stem cells (mESCs) alongside human primed pluripotent stem cells (hPSCs). “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 and laterally transferred mRNAs based on genetic sequence differences between mice and humans,” explains Takebe.

Using this experimental system, coupled with RNA imaging analysis and mouse-specific gene expression analysis, the team revealed that mRNA from mESCs moved into hPSCs during co-culture. An in-depth analysis of this transferred mRNA revealed that mRNAs coding for molecules related to transcription, translation, and stress response were transferred from mouse cells to human cells. They also proved that this mRNA transfer occurred through tunnel-like membrane extension structures, called “tunneling nanotubes,” formed between mouse and human cells.

Next, the researchers investigated the biological effects that this transferred mRNA had on the receiving cells. Notably, they found that primed hPSCs could be reverted to a so-called “naïve” state. In other words, the human cells reverted to an earlier embryonic stage in their differentiation. This suggests that mRNA moving between different mammalian stem cells has biologically significant effects beyond mere movement, going as far as cell fate conversion. The team also identified several key transcription factors involved in this process, with essential functions for pluripotent state maintenance.

Taken together, the results of this study shed light on the importance of intercellular mRNA transfer. First author Yoneyama says,“This study provides insights into a novel mechanism of intercellular communication, illustrating how cell populations coordinate and coexist with their surrounding environment, thereby advancing our understanding of biological phenomena.” Takebe concludes, “We expect our findings to contribute to the development of new cell-fate control technology that does not rely on artificial gene introduction or chemical compounds.” Such technologies could lead to new therapeutic strategies in regenerative medicine and novel drugs.

Further efforts will be needed to fully grasp the intricacies of cell-to-cell communication, and Takebe’s group is already looking forward to pursuing this exciting line of research.

Authors:

Yosuke Yoneyama^1,2, Ran-Ran Zhang^3,4,5, Mari Maezawa¹, Hideki Masaki⁶, Masaki Kimura^3,4,5, Yuqi Cai^3,4,5, Mike Adam^3,4,5, Sreeja Parameswaran⁷, Naoaki Mizuno⁶, Joydeep Bhadury⁸, So Maezawa⁹, Hiroshi Ochiai¹⁰, Hiromitsu Nakauchi^6,8, S. Steven Potter^3,4,5, Matthew T. Weirauch^3,4,5,7,11, and Takanori Takebe^{1,2,3,4,5,11,12,13}

Title:

Intercellular mRNA transfer alters the human pluripotent stem cell state

Journal:

Proceedings of the National Academy of Sciences

DOI:

10.1073/pnas.2413351122

Affiliations:

¹Human Biology Research Unit, Institute of Integrated Research, Institute of Science Tokyo, Japan
²Department of Genome Biology, Graduate School of Medicine, Osaka University, Japan
³Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, USA
⁴Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, USA
⁵Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, USA
⁶Stem Cell Therapy Division, Institute of Integrated Research, Institute of Science Tokyo, Japan
⁷Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, USA
⁸Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, USA
⁹Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Japan
¹⁰Division of Gene Expression Dynamics, Medical Institute of Bioregulation, Kyushu University, Japan
¹¹Department of Pediatrics, University of Cincinnati College of Medicine, USA
¹²Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children’s Hospital Medical Center, USA
¹³World Premier International Research Center Initiative Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Japan

• TAKEBE Takanori | Science Tokyo Research Information DB
• Takebe Laboratory
• Institute of Integrated Research | Science Tokyo organization | About Science Tokyo
• Graduate School of Medical and Dental Sciences | Science Tokyo organization | About Science Tokyo

• Osaka University (WPI-PRIMe)