The Key Role of ACE2 in Placental Development

In the field of medical research, ACE2 has attracted much attention as a receptor for SARS-CoV-2. It is also of great significance during pregnancy. The circulating level of ACE2 in pregnant women is higher than that in non-pregnant women, and the expression and genetic variation of ACE2 are closely related to various pregnancy diseases such as preeclampsia and fetal growth restriction. Recently, a research article titled "Genetically edited human placental organoids cast new light on the role of ACE2" published in Cell Death Dis constructed a placental organoid model through gene editing technology, and deeply explored the mechanism of action of ACE2 in placental development.

The researchers obtained placental tissue from women in early pregnancy and isolated trophoblast stem cells (TSCs). Subsequently, they used gene editing technology to divide TSCs into two groups. One group was the ACE2 knockout group, and the other group was different genotype groups (CC, CT, TT) carrying the ACE2 rs2074192 gene mutation, and the corresponding placental organoids were cultivated. Next, the researchers conducted multi-faceted tests and analyses on these organoids to explore the role of ACE2.

In the study of ACE2 knockout placental organoids, a series of significant changes were found. From the gene and protein level, after ACE2 knockout, the expression of ACE2 mRNA and protein in the organoids decreased significantly. Compared with normal organoids, the cell proliferation rate of the knockout group slowed down significantly, the migration ability weakened, and the cell death rate increased significantly. This shows that ACE2 is essential for the growth and survival of placental cells. In terms of organoid morphology, ACE2 knockout caused the organoid diameter to become smaller, the growth was no longer symmetrical, and it showed an abnormal structure. This means that the absence of ACE2 seriously affects the normal development of placental organoids.

Figure 1. ACE2 KO organoid growth and trophoblast cell differentiation. (Arthurs A L, et al., 2025)

Next, the researchers observed placental organoids carrying the ACE2 rs2074192 gene variant. Among them, the organoids with the TT genotype showed unique characteristics. In terms of gene and protein expression, the TT genotype organoids had significantly higher ACE2 mRNA and protein expression than the CC and CT genotypes. However, strangely, despite the increase in ACE2 protein, the enzymatic activity of ACE2 was significantly reduced. From the growth of the organoids, the diameter of the TT genotype organoids was smaller than that of the CC genotype, and the symmetry of growth was not as good as that of the CC and CT genotypes. This shows that although the TT genotype of ACE2 rs2074192 increases the expression of ACE2, it has a negative impact on the growth of placental organoids by reducing enzyme activity.

These findings indicate that ACE2 plays an indispensable role in the development of the placenta. It not only affects the growth, proliferation and survival of placental cells, but also plays a key regulatory role in the size, morphology and symmetry of placental organoids. Once the balance between ACE2 and ACE is broken, whether it is ACE2 deficiency (such as knockout model) or changes in ACE2 expression and activity caused by specific gene mutations (such as rs2074192 TT genotype), it will impair the normal development of the placenta.

Overall, this study successfully constructed a placental organoid model with ACE2 knockout and specific gene mutations for the first time, providing us with a new perspective to understand the role of ACE2 in placental development. In the future, male samples need to be included in the study to further clarify the differences in the role of ACE2 in placental development of fetuses of different genders. However, it is undeniable that the research results have laid a solid foundation for the subsequent in-depth exploration of the mechanism of placental development, prevention and treatment of related pregnancy diseases, and are expected to bring new breakthroughs in improving maternal and child health.