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Endogenous retroviruses reshape early development of human-animal chimeras

ABSTRACT: The experiments to demonstrate interspecies chimerism open the possibility of a new era of regenerative medicine growing human organs in large animals. However, currently available human pluripotent stem cells (hPSCs) are inefficient at generating human-animal chimeras for reasons unknown, indicating that developmental obstacles need to be overcome. Here, we uncover the diverse roles of primate-specific endogenous retroviruses in early development of human-mouse chimeras. By optimizing culture conditions, we generate a novel hPSC line mimicking human preimplantation epiblast with improved interspecies chimeric competency. This stem cell line is characterized by the hyper-transcription of primate-specific human endogenous retrovirus-H (HERVH). The human-specific protein ESRG, derived from HERVH, represses de novo L1 retrotransposition to safeguard hPSC genome stability that improves the developmental ability and chimeric ratio of preimplantation embryos. However, in contrast, the human-specific endogenous retrovirus-K (HERVK) released from hPSCs affects mouse trophectoderm, and impairs placentation, resulting in compromised implantation of human-mouse chimeras. Antiretroviral treatment on hPSCs for a short time before injection into mouse embryos, rescues the placentation of chimeric embryos with implantation frequency improved. Taken together, our study reveals the important but diverse roles of endogenous retroviruses in interspecies chimerism, and provides a strategy to overcome developmental obstacles in human-animal chimeric embryos.

ORGANISM(S): Mus musculus

PROVIDER: GSE168228 | GEO | 2026/03/01

REPOSITORIES: GEO

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