Abstract
INTRODUCTION: Despite of numerous studies of the placenta, some molecular and cellular characteristics, particularly the relationship among different cell types, have not been well understood. We aim to investigate the basic and intricate details of cellular and molecular elements in early and late phase placentas to gain better understanding of the immune regulation of human reproductive process. METHODS: A novel combination of techniques of spatial transcriptomics(ST), multiple immunohistochemistry, and a dual labeling combining immunohistochemistry and (fluorescence in situ hybridization) FISH on normal and ectopic pregnancy and animal models was employed to investigate the placenta at tissue, cell, protein and molecular levels and to trace the fetal and maternal origin of every cell in early and late placentas. RESULTS: Original discoveries include early expression of immune checkpoint proteins in embryo trophoblasts even before implantation. The detailed distributional relationships among different cell types of fetal and maternal origins in placenta and decidua indicate an immune rejection of the mother towards the fetus and this was counterbalanced by immune inhibitory proteins and blocking antibody Immunoglobulin G4 (IgG4) at the junction between the fetus and the mother. In contrary to common believe, we found that vascular endothelial and glandular epithelial cells in the decidua remain maternal in origin and were not replaced by fetal cells. At term placenta, fetal immune cells infiltrated into the maternal side of the decidus and vice versa indicating a possible immune reaction between fetal and maternal immune systems and suggesting a possible immune mechanism for trigger of parturition. The ability of trophoblasts to create an immune suppressed environment was also supported by findings in ectopic pregnancy and the animal models. CONCLUSION: The findings indicate a fetus-driven mechanism of immune balance involving both cellular and humoral immunity in human reproduction.