Dysregulated differentiation kinetics underlie the essential role of DNA damage repair in placental development.

The placenta orchestrates maternal-fetal exchanges, and its dysfunction compromises pregnancy outcomes. Somatic cell nuclear transfer (SCNT) placentas offer a model to investigate such dysfunction. However, SCNT placentas exhibit severe pathological features that remain poorly understood. Using single-nucleus multi-omics profiling, we uncover defective differentiation programs in SCNT placentas, including the persistent multipotency of arrested trophoblast precursors and an aberrant differentiation trajectory in the junctional zone. In addition, SCNT placentas demonstrate impaired VEGF signaling, which subsequently compromises labyrinthine vascularization. Mechanistically, we identify reprogramming-induced DNA damage as a core driver of these defects. Furthermore, we trace this genomic instability to the loss of donor cell-inherited H3K27me3 protection, an epigenetic deficiency that correlates with specific DNA damage-associated regions. Consistently, enhancing DNA damage repair pathways restores proper trophoblast differentiation kinetics and vascular transport capacity. Collectively, our study reveals that genomic instability acts as a barrier to placental development, providing a molecular framework to understand compromised placental function.