Inter-cellular mRNA Transfer Alters Human Pluripotent Stem Cell State

Yoneyama, Y.; Zhang, R.-R.; Kimura, M.; Cai, Y.; Adam, M.; Parameswaran, S.; Hideki, M.; Mizuno, N.; Bhadury, J.; Maezawa, S.; Ochiai, H.; Nakauchi, H.; Potter, S.; Weirauch, M. T.; Takebe, T.

doi:10.1101/2024.06.27.600209

bioRxiv · 10.1101/2024.06.27.600209

Inter-cellular mRNA Transfer Alters Human Pluripotent Stem Cell State

Yoneyama, Y.·Zhang, R.-R.·Kimura, M.·Cai, Y.·Adam, M.·Parameswaran, S.·Hideki, M.·Mizuno, N.·Bhadury, J.·Maezawa, S.·Ochiai, H.·Nakauchi, H.·Potter, S.·Weirauch, M. T.·Takebe, T.

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Abstract

Inter-cellular transmission of mRNA is being explored in mammalian species using immortal cell lines (1-3). Here, we uncover an inter-cellular mRNA transfer phenomenon that allows for the adaptation and reprogramming of human primed pluripotent stem cells (hPSCs). This process is induced by the direct cell contact-mediated coculture with mouse embryonic stem cells (mESCs) under the condition impermissible for human primed PSC culture. Mouse-derived mRNA contents are transmitted into adapted hPSCs only in the coculture. Transfer-specific mRNA analysis show the enrichment for divergent biological pathways involving transcription/translational machinery and stress-coping mechanisms, wherein such transfer is diminished when direct cell contacts are lost. After 5 days of mESC culture, surface marker analysis, and global gene profiling confirmed that mRNA transfer-prone hPSC efficiently gains a naive-like state. Furthermore, transfer-specific knockdown experiments targeting mouse-specific transcription factor-coding mRNAs in hPSC show that mouse-derived Tfcp2l1, Tfap2c, and Klf4 are indispensable for human naive-like conversion. Thus, inter-species mRNA transfer triggers cellular reprogramming in mammalian cells. Our results support that episodic mRNA transfer can occur in cell cooperative and competitive processes(4), which provides a fresh perspective on understanding the roles of mRNA mobility for intra- and inter-species cellular communications.

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Yoneyama, Y., Zhang, R.-R., Kimura, M., Cai, Y., Adam, M., Parameswaran, S., Hideki, M., Mizuno, N., Bhadury, J., Maezawa, S., Ochiai, H., Nakauchi, H., Potter, S., Weirauch, M. T., Takebe, T.. 2024-06-27. Inter-cellular mRNA Transfer Alters Human Pluripotent Stem Cell State. https://doi.org/10.1101/2024.06.27.600209

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