Nr1h2: A key transcription factor unlocks new potential in stem cell-based embryo models

SINGAPORE – Researchers from the A*STAR Institute of Molecular and Cell Biology (IMCB), led by Dr Jonathan Yuin-Han Loh, have identified Nr1h2, a critical transcription factor essential for early embryo development. Published in Nature Communications, their findings enhance our understanding of gene regulation during blastoid formation and hold promise for regenerative medicine, fertility treatments, and developmental biology research.

At the earliest stages of life, the blastocyst—a highly organised structure critical for implantation—begins to form. Its development is tightly controlled by genetic and epigenetic programs. Stem cell-based embryo models, such as blastoids, serve as models of the blastocyst and are invaluable tools for studying embryogenesis and early human development. However, the variability in blastoid induction has limited their utility, due to a limited understanding of the genetic drivers of blastoid formation.

Dr Loh’s team addressed this gap by uncovering the role of Nr1h2 in regulating stem cell fate and driving high-quality blastoid formation. Using a loss-of-function screen, the researchers pinpointed Nr1h2 as a key transcription factor conserved across mammalian species. Nr1h2 activation was sufficient to enhance the functional and genetic fidelity of stem cell-derived embryo models.

To test Nr1h2’s potential, the team treated embryonic stem cells with the small-molecule agonist T0901317. The treated cells, termed NrESCs, exhibited expanded pluripotency, expressing canonical markers and generating both embryonic and extra-embryonic lineages. Transcriptomic and epigenetic analyses showed that NrESC-derived blastoids closely resembled natural blastocysts, surpassing current EPSC-derived models in genetic and physiological fidelity.

“Nr1h2 activation rewires embryonic stem cells into an expanded pluripotent state, creating a robust platform to study early developmental processes and identify therapeutic targets,” said Dr Loh.

Therapeutic Potential for Reproductive Health

The discovery also has profound implications for reproductive health. Trophectoderm cells, essential for implantation, were more physiologically faithful in NrESC-derived blastoids. When transferred into mice, these blastoids achieved significantly higher implantation rates compared to EPSC-derived counterparts. Nr1h2 activation also enhanced blastocyst generation in both mice and pigs, suggesting a highly conserved mechanism across species.

Nr1h2’s identification as a master regulator of early embryogenesis opens new avenues for developmental biology. By refining stem cell-based embryo models, this discovery supports the design of targeted therapies, advances regenerative medicine, and improves our ability to explore the earliest stages of life. The team’s work sets the stage for future research into transcriptional networks and their role in lineage determination.

“Stem cell-based embryo models are revolutionising drug discovery and reproductive biology,” Dr Loh explained. “Our findings demonstrate that activating Nr1h2 enhances the fidelity of these models, providing an innovative approach to tackle developmental disorders, infertility, and beyond.”

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