Transplantation of umbilical cord-derived mesenchymal stem cells promotes the recovery of thin endometrium in rats

Abstract

The endometrium plays a critical role in embryo implantation and pregnancy, and a thin uterus is recognized as a key factor in embryo implantation failure. Umbilical cord mesenchymal stem cells (UC-MSCs) have attracted interest for the repair of intrauterine adhesions. The current study investigated the repair of thin endometrium in rats using the UC-MSCs and the mechanisms involved. Rats were injected with 95% ethanol to establish a model of thin endometrium. The rats were randomly divided into normal, sham, model, and UC-MSCs groups. Endometrial morphological alterations were observed by hematoxylin–eosin staining and Masson staining, and functional restoration was assessed by testing embryo implantation. The interaction between UC-MSCs and rat endometrial stromal cells (ESCs) was evaluated using a transwell 3D model and immunocytochemistry. Microarray mRNA and miRNA platforms were used for miRNA-mRNA expression profiling. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed to identify the biological processes, molecular functions, cellular components, and pathways of endometrial injury and UC-MSCs transplantation repair and real-time quantitative reverse transcription PCR (qRT-PCR) was performed to further identify the expression changes of key molecules in the pathways. Endometrium thickness, number of glands, and the embryo implantation numbers were improved, and the degree of fibrosis was significantly alleviated by UC-MSCs treatment in the rat model of thin endometrium. In vitro cell experiments showed that UC-MSCs migrated to injured ESCs and enhanced their proliferation. miRNA microarray chip results showed that expression of 45 miRNAs was downregulated in the injured endometrium and upregulated after UC-MSCs transplantation. Likewise, expression of 39 miRNAs was upregulated in the injured endometrium and downregulated after UC-MSCs transplantation. The miRNA-mRNA interactions showed the changes in the miRNA and mRNA network during the processes of endometrial injury and repair. GO and KEGG analyses showed that the process of endometrial injury was mainly attributed to the decomposition of the extracellular matrix (ECM), protein degradation and absorption, and accompanying inflammation. The process of UC-MSCs transplantation and repair were accompanied by the reconstruction of the ECM, regulation of chemokines and inflammation, and cell proliferation and apoptosis. The key molecules involved in ECM-receptor interaction pathways were further verified by qRT-PCR. Itga1 and Thbs expression decreased in the model group and increased by UC-MSCs transplantation, while Laminin and Collagen expression increased in both the model group and MSCs group, with greater expression observed in the latter. This study showed that UC-MSCs transplantation could promote recovery of thin endometrial morphology and function. Furthermore, it revealed the expression changes of miRNA and mRNA after endometrial injury and UC-MSCs transplantation repair processed, and signaling pathways that may be involved in endometrial injury and repair.

Role of noncoding RNA in the pathophysiology and treatment of intrauterine adhesion

“…After confirming that umbilical cord mesenchymal stem cells (UCMSCs) can improve uterine appearance and morphological characteristics, a study analyzed the differential expression of miRNAs in the IUA model group and the MSCs treatment group ( Zhang et al, 2022b ). Compared with the model group, 55 miRNAs were up-regulated and 59 miRNAs were down-regulated in the treatment group.…”

Fibroblast activation during decidualization: Embryo-derived TNFα induction of PGI2-PPARδ-ACTIVIN A pathway through luminal epithelium

“…IUA can interfere with the embryo's implantation and development, resulting in decreased or even full loss of intrauterine volume, female infertility, and recurrent miscarriages [76]. The thin endometrial model exhibits a higher degree of fibrosis than normal controls, which is thought to be a crucial component in embryo implantation failure [77]. The key question is why fibrosis doesn't occur during normal early pregnancy?…”

Bone Marrow- and Umbilical Cord-Derived Mesenchymal Stem Cell Secretome Alters Gene Expression and Upregulates Motility of Human Endometrial Stromal Cells

“…The copyright holder for this preprint this version posted November 14, 2022. ; https://doi.org/10.1101/2022.11.12.516251 doi: bioRxiv preprint differentiation into endometrial cell types (13)(14)(15)(16). The secretome and biological characteristics of MSCs vary based on tissue source (17,18); however, both BM-MSCs and UC-MSCs promote endometrial regeneration in rodent models (12).…”

“…Studies with rodent models and small clinical trials have shown that nonhematopoietic MSCs from different tissue sources can contribute to endometrial repair after injury (12). In rat models of endometrial injury, BM-MSCs and umbilical cord (UC) MSCs aid endometrial repair through paracrine actions on the endometrium as well as differentiation into endometrial cell types (13)(14)(15)(16). The secretome and biological characteristics of MSCs vary based on tissue source (17,18); however, both BM-MSCs and UC-MSCs promote endometrial regeneration in rodent models (12).…”