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.

SFRP4+ stromal cell subpopulation with IGF1 signaling in human endometrial regeneration

“…Previous studies have shown that endometrial stem/progenitor cells and endometrial mesenchymal stem cells are responsible for the regeneration of human and mouse endometria 2 , 28 . As there was an increasing attention on fibroblasts heterogeneity and functions in this field, fibroblasts were suspected to participate in tissue health and diseases through physical or biochemical niches by producing extracellular matrix or soluble signal molecules 29 .…”

“…As there was an increasing attention on fibroblasts heterogeneity and functions in this field, fibroblasts were suspected to participate in tissue health and diseases through physical or biochemical niches by producing extracellular matrix or soluble signal molecules 29 . One of the populations being largely proposed as a regenerative population in the endometrium is the stromal SUSD2 + , associated to perivascular areas 2 , 28 , so we checked the SUSD2 + cells in our data (Supplementary Fig. S11 c, d), and found SUSD was highly enriched in the vascular cell population (ADIRF + vascular cells) (Supplementary Fig.…”

The link between intrauterine adhesions and impaired reproductive performance: a systematic review of the literature

“…Cyclic regeneration of the endometrium is regulated and promoted by stem cells (Fig. 3 ), located near the spiral arteries of the endometrium [ 46 , 47 ]. The stem cells may differentiate into stromal and epithelial cells and contribute to the maintenance of the endometrium [ 47 , 48 ].…”

“…In the case of IUAs, the endometrium is characterized by endometrial fibrosis: normal, hormonally responsive endometrial tissue is replaced by atrophic, avascular and unresponsive scar tissue [ 2 , 5 , 47 , 49 , 57 ]. Both the damaged endometrium and the surrounding endometrium are different from the normal endometrium [ 23 ].…”

“…Regeneration and repair of a damaged endometrium remains a clinical challenge. Various cell based therapies have been proposed as an alternative treatment approach in women with IUAs [ 47 , 100 , 101 ]. Stem cells derived from various tissues, platelet-rich plasma and growth factors may be effective alternatives to regenerate the refractory endometrium either through direct endometrium differentiation or paracrine effects [ 47 , 100 , 101 ].…”