Uterine Stem Cells and Benign Gynecological Disorders: Role in Pathobiology and Therapeutic Implications

Malak El Sabeh, Sadia Afrin, Bhuchitra Singh, Mariko Miyashita‐Ishiwata, Mariko Miyashita-Ishiwata, Miyashita-Ishiwata M, Mostafa A. Borahay
Stem cell reviews and reports · 2020 · vol. 17(3) , pp. 803–820 · doi:10.1007/s12015-020-10075-w · PMID:33155150 · PMC8096869 · W3097748768
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⚙ AI-generated summary by gemini-2.5-flash-lite+body, 2026-06-13 ⓘ

This review summarizes the role of uterine stem cells in the pathogenesis of benign gynecologic conditions and explores their therapeutic potential in regenerative medicine.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 · read from full text ⓘ

This comprehensive review examined evidence that stem cells in the endometrium and myometrium, and related bone marrow stem cells, contribute to the pathobiology of benign gynecological disorders, focusing particularly on proposed “stem cell to tumor-initiating stem cell” transitions in leiomyomas, endometriosis, and adenomyosis, and associated genetic/epigenetic alterations. It synthesized human and animal studies identified via database searches through September 2020, describing stem-cell marker phenotypes, niche features such as hypoxia, and examples including MED12-mutant leiomyoma stem cells and hypomethylating effects in experimental settings. A major caveat the review emphasizes is methodological uncertainty and limited specificity in stem cell isolation approaches (e.g., toxicity/sensitivity of Hoechst dye–based assays), alongside the overall incompletely understood nature of these disorders’ mechanisms. This paper is centrally about endometriosis and adenomyosis within a broader review of uterine stem cells’ roles in benign gynecological disorders—specifically summarizing mechanisms of stem cell involvement in endometriosis and adenomyosis pathogenesis.

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Abstract

Stem cells in the endometrium and myometrium possess an immense regenerative potential which is necessary to maintain the menstrual cycle and support pregnancy. These cells, as well as bone marrow stem cells, have also been implicated in the development of common benign gynecological disorders including leiomyomas, endometriosis and adenomyosis. Current evidence suggests the conversion of uterine stem cells to tumor initiating stem cells in leiomyomas, endometriosis stem cells, and adenomyosis stem cells, acquiring genetic and epigenetic alterations for the progression of each benign condition. In this comprehensive review, we aim to summarize the progress that has been made to characterize the involvement of stem cells in the pathogenesis of benign gynecologic conditions which, despite their enormous burden, are not yet fully understood. We focus on the stem cell characteristics and aberrations that contribute to the development of benign gynecological disorders and the possible clinical implications of what is known so far. Lastly, we discuss the role of uterine stem cells in the setting of regenerative medicine, particularly in the treatment of Asherman syndrome.Graphical abstract.
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Stem

Uterine adenomyosis is a benign condition in which endometrial glands and stroma invade the uterine musculature resulting in hypertrophic and hyperplastic myometrium, producing a diffusely enlarged uterus [ 163 , 164 ]. This condition is described as focal when a circumscribed nodular collection is identified or diffuse when different groups of glands are distributed throughout the myometrium [ 165 , 166 ]. Adenomyosis can be asymptomatic, but the most common symptom is heavy menstrual bleeding; symptoms can also include dysmenorrhea and chronic pelvic pain [ 167 , 168 ]. Sex steroid aberrations, neuro-angiogenesis, inflammation, and altered cell proliferation have been implicated in the development of adenomyosis, but the precise pathogenesis is still unknown [ 169 ]. Several hypotheses have been proposed, one of which is the invagination of the endometrial basalis layer in response to steroid hormones, hyperperistalsis, and the activation of the tissue injury and repair mechanism [ 170 ]. An alternative hypothesis is the metaplasia of displaced embryonic pluripotent Mullerian remnants or the differentiation of adult stem cells [ 170 ]. The Mullerian ducts share common embryological structures during fetal life, maturing to form the female uterine tract and differentiating into stroma and endometrial glands [ 171 ]. Metaplastic alterations of the intra-myometrial embryonic pluripotent Mullerian remnants form de novo ectopic endometrial tissue inside the myometrial wall, resulting in the development of adenomyotic lesions [ 163 ]. García-Solares et al. proposed that progenitor stem cells can be deposited in the peritoneal cavity after retrograde menstruation and differentiate into stroma and endometrial glands. These may then progress into de novo intra-myometrial endometrial implants and form an endometrial colony which leads to focal uterine adenomyosis [ 170 ]. Endometrial stem cells may also be activated by tissue injury, causing stem cell niche disruption and allowing them to differentiate into progenitor cells which subsequently invade the myometrium, progressing to adenomyosis [ 172 ]. Adenomyosis derived stem cells are not well understood. Adenomyosis-derived mesenchymal stem cells have previously been isolated from adenomyotic tissue [ 173 ]. These stem cells differentiated into mesodermal lineages and expressed MSCs surface markers and had a similar morphology, phenotype, and potential of multilineage differentiation compared to endometrial MSCs [ 173 ]. They exhibited high COX-2 expression compared to endometrial mesenchymal stem cells, highlighting the potential role of` COX-2 in the pathogenesis of adenomyosis [ 173 ]. Lupicka et al demonstrated increased mRNA expression of pluripotency markers, such as OCT4, NANOG, and SOX2 in bovine adenomyotic lesions compared to normal uteri [ 174 ]. Moreover, Musashi-1, an adult stem cell marker, was remarkably higher in eutopic and ectopic endometria from patients with adenomyosis in contrast to normal endometrium [ 175 ]. Further studies are needed to identify the functions and mechanisms of Musashi-1 in the development of adenomyosis. Ibrahim et al. identified intraepithelial pale cells at the interface of the endometrial-myometrial junction that actively migrated into the stroma in adenomyosis [ 176 ]. This group hypothesized that these cells may migrate into the stroma of the basal endometrium and into the myometrium, possibly facilitated by the high concentration of matrix metalloproteinases [ 176 – 178 ]. Numerous advanced medical approaches have been developed for adenomyosis; however, more satisfactory treatment options are needed. More research is required to identify the properties of endometrial or progenitor stem cells that ultimately result in the migration and invasion of endometrial tissue into the myometrium to develop adenomyosis. Understanding the function and mechanism of stem cells in the initiation and progression of adenomyosis may generate new, targeted treatment strategies. For example, treatment with a COX-2 inhibitor suppressed migration and invasion and induced apoptotic capabilities of adenomyosis mesenchymal stem cells [ 173 ].

Search

A comprehensive search of PubMed, Embase, Scopus, and Cochrane databases up to September 2020 was conducted to identify peer-reviewed literature. We used the following keywords: uterine fibroid/leiomyoma, endometriosis, adenomyosis, stem cells, and progenitor cells. Screening of studies was done by two authors (ME and SA). Results were further reviewed by the senior author (MAB). Articles were initially screened based on title and abstract, and a second round of screening was done after reading the full-text articles. We only included articles in the English language. This review included studies in both humans and animals.

Concluding

Our understanding of stem cells in the uterus and their role in the reproductive system has expanded considerably since their discovery. The developing knowledge on the stem cell niches and drivers of pathologic development in the different benign gynecologic conditions is opening doors for several therapeutic options. Moreover, the high regenerative capacity of these stem cells offers potential therapeutic promise for conditions such as Asherman syndrome and exciting prospects for other reproductive and non-reproductive pathologies, with some of these therapies being currently tested. However, many questions remain to be addressed in future research to make these advancements a therapeutic reality.

Introduction

Stem cells are undifferentiated cells that are present in many tissues and are capable of reproducing themselves and differentiating into different cell types. They proliferate, through asymmetric division, to replace themselves and give rise to transient amplifying progenitors [ 1 , 2 ]. Progenitor cells multiply in large numbers, differentiate into tissue-specific cells, and have a lesser ability to self-renew [ 2 ]. The terms stem cells and progenitor cells have been used interchangeably to describe cells with proliferating potential [ 3 ]. Stem cells are usually present in the G 0 phase (quiescent state) of the cell cycle and are located in an environment known as the niche [ 4 ]. Embryonic stem cells were first identified in 1981 in the mouse embryo [ 5 ], and it was not until more than 20 years later that colony forming cells were identified in the endometrium [ 6 ]. Since then, studies have looked into stem cells in the uterus as well as stem cell contributions from the bone marrow. These cells are studied in the context of the normal physiology of the reproductive system as they are involved in the monthly regeneration of the endometrium during menses and sustaining pregnancy. They were also studied in the context of the development of benign and malignant gynecologic conditions. Understanding the aberrations that lead to the transformation of endometrial and myometrial stem cells that drive the development of leiomyomas, endometriosis, and adenomyosis are crucial to establish targeted therapeutic options for these conditions. In this comprehensive review, we aim to summarize the involvement of stem cells in the pathogenesis of benign gynecologic conditions that, despite their enormous burden, are not yet clearly understood. We focus on the stem cell characteristics and aberrations that contribute to the development of these conditions and the potential clinical implications of stem cell involvement. Lastly, we discuss the role of uterine stem cells in the setting of regenerative medicine, highlighting the studies where stem cells were used for the treatment of Asherman syndrome.

Regenerative

Asherman syndrome (AS) is a complex gynecological disorder defined by the presence of endometrial destruction and intrauterine adhesions resulting in hypomenorrhea or amenorrhea, infertility, recurrent miscarriages and abnormal placentation [ 179 , 180 ]. The incidence of this condition ranges in different countries and is directly influenced by the number of abortions performed, the incidence of genital tuberculosis, as well as the criteria used to detect the adhesions [ 181 ]. A meta-analysis reporting on women evaluated with hysteroscopy within 12 months following spontaneous abortion (of which 86% underwent a curettage) showed that the prevalence of AS was 19.1% [ 182 ]. Treatment of AS is only suggested if the patient has infertility issues or clinical symptoms. Multiple hysteroscopic techniques, hormone therapy and intrauterine devices insertion are the most common treatments available for the AS patients, but the treatment efficacy is not consistent and may vary from patient to patient. At present, there is immense attention to use stem cells as therapeutic options for regenerative medicine, and AS has appeared as a promising candidate for stem cell-driven regenerative treatment. It was shown that AS stem cells transplantation had a proliferative impact on the endometrium, resulting in an increased endometrium thickness, improved tissue construction, enhanced angiogenesis, and prevented gestation as well as pregnancy loss [ 183 ]. Stem cells as a treatment for AS has been explored in a limited number of animal experiments and clinical trials. On an experimental AS mouse model, stem cell recruitment and pregnancy rate were investigated after BMDCs transplantation [ 184 ]. BMDSC transplanted group had improved the fertility rate, with 90% of mice conceiving after the transplantation compared to the control group [ 184 ]. These results illustrated the functional role of BMDC in the uterine renovation. In another investigation, a combination of MSCs treatment and estrogen was tremendously effective in enhancing regeneration of endometrium in an AS rat model [ 185 ]. This therapy stimulated endometrial proliferation and angiogenesis by increasing PCNA, Ki-67 and VEGF expressions and decreasing fibrosis [ 185 ]. This field of research is not only restricted to animal models as autologous stem cells were used in patients with AS. For example, a report was published on a patient with severe AS who failed to respond after the placement of intrauterine contraceptive device [ 186 ]. Adult autologous stem cells were isolated from patient’s own bone marrow, and endometrial angiogenic stem cells were separated from adult autologous stem cells. After the placement of the endometrial angiogenic stem cells in the endometrial cavity, the patient had increased endometrial thickness, improved vascularity, and was ultimately able to sustain a pregnancy [ 186 ]. Another pilot cohort study was conducted by using autologous CD133+ BMDSCs to treat endometrial atrophy and refractory AS [ 187 ]. In this study, stem cells were injected to the endometrial stem cell niche via intra-arterial catheterization. After stem cell implantation, all the patients had increased endometrial thickness and vascular density and improved endometrium and uterine cavity that were confirmed by hysteroscopic observations [ 187 ]. In another study, sub-endometrial autologous stem cells were implanted in patients with AS followed by the supplementing with oral estrogen therapy, and endometrial thickness were assessed after few months [ 188 ]. The autologous stem cell resulted in endometrial regeneration and restoration of menstruation in five out of six patients [ 188 ]. Menstrual blood-derived stromal cells have also been confirmed to be effective for the severe AS treatment. After the transvaginal transplantation of these stem cells, followed by hormonal stimulation, all the patients had remarkable endometria proliferation, and five of the seven patients gained more than 7mm endometrial thickness, which confirmed acceptability of embryo implantation [ 189 ]. Four patients went through frozen embryo transfer, after which two of them conceived, and one of them experienced spontaneous pregnancy after second transplantation [ 189 ]. Limitations are expected when using the stem cells for regenerative medicine. While stem cells enhanced the proliferation and renewal of normal or injured endometrium, they also have the ability to promote ectopic endometrial growth or endometriosis, as discussed above [ 141 ]. Stem cells and cancer cells have some common traits such as self-renewal capability, high proliferative and elasticity ability [ 190 ]. BMDCs may also result in endometriosis and cancer development [ 191 ]. Having said that, there is tremendous promise in stem cell therapy in regenerative medicine and in the restoration of injured tissues for which there are currently few therapeutic options. To increase the stem cells retention in the body, scientists have linked biocompatible and biodegradable materials such as hydrogel, scaffolds and nanostructure lipid carrier with stem cells or stem cell by-products. In a phase I clinical trial, collagen scaffold was used as an effective carrier for holding the umbilical cord-derived MSCs to prevent recurrent intrauterine adhesion after separation surgery [ 192 ]. Hormone replacement therapy was also used to stimulate a natural menstrual cycle. After the treatment, successful endometrial and angiogenic proliferation was evaluated, and ten out of the twenty-six patient became pregnant. The trial lacked a control group, making it difficult to identify whether the surgery, the stem cells loaded with collagen scaffold, the hormone treatment, or a combination made an alteration. Linking stem cells with biomaterials seems to be a very hopeful strategy to treat AS, but more research work is required. Moreover, secreted extracellular vesicles from umbilical cord-derived mesenchymal stem cells was used, with estrogen, to treat AS in an animal model [ 193 ]. Endometrial regeneration and decreased fibrotic appearance were observed after the treatment. More research is warranted to fill up the gaps in order for this research to be useful in fertility treatment.

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Condition tags

endometriosis

MeSH descriptors

Adenomyosis Adenomyosis Endometriosis Endometriosis Endometriosis Leiomyoma Leiomyoma Leiomyoma Female Humans Myometrium Myometrium Neoplastic Stem Cells Neoplastic Stem Cells Pregnancy

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