Ciliary IFT-B Transportation Plays an Important Role in Human Endometrial Receptivity Establishment and is Disrupted in Recurrent Implantation Failure Patients

Abstract

The lack of accurate understanding of cellular physiology and pathophysiology during the WOI constitutes the major obstacle to correct diagnosis and treatment for patients with recurrent implantation failure (RIF). The role of cilia as one of the key organelles in endometrial epithelium has been poorly understood during embryo implantation. In this study, the morphological and molecular changes of endometrial cilia regulated by hormones were demonstrated in endometrial epithelial organoid models. Multi-omics studies revealed highly relevant cilia-related activities like cilia movement during endometrial receptivity establishment. Interestingly, both in vitro model and in vivo patient data have shown that the apical part of cilium formed a cilia-derived spherical structure after hormone stimulation. We also found intraflagellar transport (IFT) train multi-subunit complex B (IFT-B) was aggregated in the sphere during the implantation window. Meanwhile mitochondria localization signal increased at the cilia basement. Proteomics and the functional assay showed the deficiency of energy metabolism in RIF patients and cilia formation abnormalities. The abnormal energy supply resulted in the failure of vesicle transport by deficiency of IFT-B location, ultimately leading to the failure of receptivity establishment. Our study revealed the essential role of endometrial cilia in embryo implantation and indicated that mitochondrial metabolism was crucial for normal ciliogenesis and embryo implantation.