To overcome this, we developed a new platform for reproductive engineering based on a transient reprogramming strategy that “rewinds” conventional human embryonic stem cells to an earlier developmental state. This time-reversed state mimics the molecular and epigenetic features of the pre-implantation embryo, a highly plastic cell population that retains the potential to generate both embryonic and extraembryonic tissues. We call this approach a differentiation slingshot: rather than pushing stem cells forward along a fixed path, we first return them to a more naive, lineage-unbiased state before directing differentiation. This enables more precise control over fate outcomes, with a particular advantage in modeling the earliest developmental bifurcations.
Using this system, we established a robust in vitro model for human placenta development by guiding slingshot cells toward the trophoblast lineage—the precursor of the placenta. These cells express key markers of placental subtypes, form epithelial structures, and exhibit functional behaviors reminiscent of early implantation. Importantly, they do so in a scalable, defined, and reproducible system that avoids the ethical and technical constraints associated with using human embryos or explants. To further explore embryo-uterine interactions, we pair this model with an engineered endometrial interface that recapitulates the molecular and physical environment of the uterine lining. This allows us to study tissue-tissue communication, adhesion, and early signaling events in a fully human context. We also integrate CRISPR-based perturbations and single-cell transcriptomic profiling to dissect the signaling pathways and transcriptional programs that drive lineage commitment and tissue patterning.
Together, this platform establishes a new paradigm for reproductive engineering: by rewiring the transcriptional and epigenetic landscape of human stem cells, we can recreate critical developmental transitions in vitro and study how cell-intrinsic programs and environmental cues interact. In the long term, this approach could enable applications in fertility research, early pregnancy diagnostics, and even regenerative medicine, where cell types derived from this system may be used to model disease or contribute to tissue repair.
This work brings a synthetic and engineering perspective to human development—a traditionally descriptive field—by reframing early embryogenesis as a controllable, designable process.
For the chemical engineering community, this represents a growing frontier: the ability to manipulate complex multicellular systems, steer fate trajectories, and build functional human tissues from the bottom up.