Adult stem cells in endometrial regeneration: Molecular insights and clinical applications

Abstract

Endometrial damage is an important cause of female reproductive problems, manifested as menstrual abnormalities, infertility, recurrent pregnancy loss, and other complications. These conditions are collectively termed "Asherman syndrome" (AS) and are typically associated with recurrent induced pregnancy terminations, repeated diagnostic curettage and intrauterine infections. Cancer treatment also has unexpected detrimental side effects on endometrial function in survivors independently of ovarian effects. Endometrial stem cells act in the regeneration of the endometrium and in repair through direct differentiation or paracrine effects. Nonendometrial adult stem cells, such as bone marrow-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells, with autologous and allogenic applications, can also repair injured endometrial tissue in animal models of AS and in human studies. However, there remains a lack of research on the repair of the damaged endometrium after the reversal of tumors, especially endometrial cancers. Here, we review the biological mechanisms of endometrial regeneration, and research progress and challenges for adult stem cell therapy for damaged endometrium, and discuss the potential applications of their use for endometrial repair after cancer remission, especially in endometrial cancers. Successful application of such cells will improve reproductive parameters in patients with AS or cancer. Significance: The endometrium is the fertile ground for embryos, but damage to the endometrium will greatly impair female fertility. Adult stem cells combined with tissue engineering scaffold materials or not have made great progress in repairing the injured endometrium due to benign lesions. However, due to the lack of research on the repair of the damaged endometrium caused by malignant tumors or tumor therapies, the safety and effectiveness of such stem cell-based therapies need to be further explored. This review focuses on the molecular insights and clinical application potential of adult stem cells in endometrial regeneration and discusses the possible challenges or difficulties that need to be overcome in stem cell-based therapies for tumor survivors. The development of adult stem cell-related new programs will help repair damaged endometrium safely and effectively and meet fertility needs in tumor survivors.

Keywords: Asherman syndrome; adult stem cells; endometrial cancer; endometrial regeneration.

Figure 1

Human endometrial stem cells Human endometrial stem cells (endoSCs), including endometrial epithelial progenitor cells (EEPCs), endometrial mesenchymal stem cells (eMSCs), and side population (SP) cells, have been identified in the endometrium. EEPCs are mainly located in glands of the basal layer of the endometrium. Among the stem markers in EEPCs, AXIN2 marks most epithelial cells in the basalis, N‐cadherin only the bases of the glands adjacent to the myometrium, SSEA1 and SOX9 are co‐localized and they are in the basalis (and luminal epithelium in the functionalis) and proximal to the N‐cadherin+ cells with little overlap. eMSCs are located around blood vessels in the endometrium of functional and basal layers, and exist in shedding menstrual blood, which express stem markers such as SUSD2/W5C5, CD146, and PDGFRβ. Endothelial, epithelial, and stromal SP cells have the ability to exclude the DNA‐binding dye Hoechst 33342 through the ATP‐binding cassette transporter, which express multiple types of cell markers, including high levels of undifferentiated cell markers c‐KIT and OCT‐4, endothelial cell markers CD31 and CD34, epithelial cell marker EMA, and mesenchymal stem cell marker CD90, CD105, and CD146. EndoSCs are involved in endometrial tissue regeneration. Near the rapidly growing spiral arterioles of the human endometrium, there is an area around the blood vessels, which promotes the self‐renewal of stem cells. This area has the function of a stem cell niche, which promotes endometrial cyclic regeneration. This diagram was adapted from Hum Reprod Update 2016; 22: 137‐163

Figure 2

The roles of Adult stem cells for endometrial repair. A schematic diagram was established that how adult stem cells from endometrium, bone marrow, umbilical cord, and adipose tissue repair the damaged endometrium. MenSCs, eMSCs, BMDSCs, BMDCs, hUC‐MSCs, and AD‐MSCs act in regeneration of the damaged endometrium through direct differentiation or paracrine effects. These stem cells‐mediated paracrine factors, could participate in endometrial proliferation, angiogenesis, immunomodulation, and activate the stem cell niches to maintain stemness. There is no strong evidence that eMSCs or MenSCs differentiate into ESCs and EECs. Studies showed that BMDSCs and BMDCs can differentiate into ESCs and EECs. AD‐MSCs, adipose tissue‐derived mesenchymal stem cells; BMDCs, bone marrow‐derived cells; BMDSCs, bone marrow‐derived mesenchymal stem cells; CSF1, macrophage colony‐stimulating factor 1; EECs, endometrial epithelial cells; eMSCs, endometrial mesenchymal stem cells; eNOS, endothelial nitric oxide synthase; EP2, prostaglandin E receptor; ESCs, endometrial stromal cells; HGF, hepatocyte growth factor; hUC‐MSCs, human umbilical cord‐derived mesenchymal stem cells; IGF‐1, insulin‐like growth factor 1; MenSCs, menstrual blood‐derived stem cells; SDF‐1, stromal cell‐derived factor 1; TSG6, Tumor necrosis factor‐α‐induced protein 6; VEGF, vascular endothelial growth factor. The tissue pictures used in this figure derived from https://smart.servier.com/