Biology of Reproduction, 2020, 102(6), 1153–1159

doi:10.1093/biolre/ioaa011
Review
Advance Access Publication Date: 22 January 2020

Review

The role of endometrial stem cells in the

pathogenesis of endometriosis and their

Downloaded from https://academic.oup.com/biolreprod/article/102/6/1153/5712138 by Universidad EIA user on 19 May 2021

application to its early diagnosis†
Yanli Liu1,2 , Zhiqin Zhang3 , Fen Yang1,2,4 , Hongmei Wang3 ,
Shengying Liang1,2 , Huiling Wang3 , Jun Yang3,* and Juntang Lin1,2,*
1 Stem Cell and Biotherapy Technology Research Center, College of Life Science and Technology, Xinxiang Medical

University, Xinxiang, China, 2 Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University,
Xinxiang, China, 3 The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China, and 4 College of
Biomedical Engineering, Xinxiang Medical University, Xinxiang, China
∗ Correspondence: Jun Yang, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road, Weihui, Xinxiang,

Henan 453100, China. Tel: +86 13937335562; E-mail: 13937335562@163.com; Juntang Lin, Xinxiang Medical University, East
of JinSui Road, Xinxiang, Henan 453003, China. Tel: +86 0373 3831679; E-mail: linjtlin@126.com
† Grant Support: This study was supported by the National Natural Science Foundation of China (81671619 and U1804186),

the Xinxiang Foundation (20172DCG-03 and ZD17008) and the Xinxiang Medical University Foundation
(20172DCG-03 and 2017CXY-2-12).

Received 7 October 2019; Revised 21 December 2019; Accepted 16 January 2020

Abstract
Pelvic pain, infertility, and a high postoperative recurrence rate are associated with endometriosis
and adversely affect the physical and mental health of patients. Moreover, these factors place a
heavy burden on families and society. The identification of endometrial stem cells (EnSCs) in the
eutopic endometrium, menstrual blood, and ectopic lesions of women with endometriosis not only
provides new research objects in the context of endometriosis but also promotes and improves
our understanding of its pathogenesis. Furthermore, based on previous studies, we reasonably
suppose that dysfunctions of eutopic EnSCs play a critical role in the onset of endometriosis
and directly cause abnormalities in the endometrium; subsequently, retrograde menstruation
facilitates the delivery of abnormal endometrial tissues to the ovaries and pelvic cavity, where
they ectopically implant, grow, and form ectopic lesions. Additionally, as a chronically progressive
disease, there is a delay (3–11 years) from the first onset of symptoms to the diagnosis of
endometriosis. Therefore, the development of a method for early diagnosis with high sensitivity
and specificity is essential for endometriosis patients and has the potential to enable early treat-
ment, prevent endometriosis progression, and relieve pain in patients. Thus, focusing on EnSCs
will contribute to clarifying the potential pathogenesis of endometriosis and provide support for
the application of EnSCs as therapeutic and early diagnostic targets in endometriosis treatment.

Summary sentence
Focusing on endometrial stem cells (EnSCs) will contribute to clarifying the potential pathogenesis
of endometriosis and provide support for the application of EnSCs as therapeutic and early
diagnostic targets in endometriosis treatment.
Key words: endometriosis, endometrial stem cells, pathogenesis, early diagnosis

© The Author(s) 2020. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com 1153
1154
Introduction
Endometriosis refers to endometrial tissues (glands and stroma)
that are ectopically implanted in sites outside the endometrium and
myometrium, and it is conservatively estimated that the incidence of
endometriosis in women of childbearing age is 10–15%. Currently,
the number of patients with endometriosis has exceeded 7 million
worldwide, and the incidence rate has been increasing annually [1, 2].
Current studies have demonstrated that the clinical manifestations of
endometriosis include menstrual abnormalities, dysmenorrhoea, and
pain during sexual intercourse, which are closely related to infertility.
Approximately, 50% of infertile women and 50–60% of women of
childbearing age and adolescent women with various forms of pelvic
pain are definitively diagnosed with endometriosis [3, 4]. Gener-
ally, endometriosis manifests as diverse morphologies and extensive
lesions. Although the lesions are not fatal, the presentation of cell
proliferation, infiltration, and recurrence are malignant biological
behaviors; additionally, the side effects caused by drugs and surgical
treatment and the high recurrence rate of endometriosis seriously
affect the physical and mental health of patients and place a heavy
burden to families and society [2, 5–7].
Stem cell theory of endometriosis pathogenesis
To date, the pathogenesis of endometriosis is unclear. Hypotheses
regarding its pathogenesis mainly include the following: endometrial
ectopic implantation caused by retrograde menstruation, coelomic
metaplasia, embryonic cell rest, induction followed by lymphatic and
vascular dissemination, endocrinological factors, immunological and
genetic factors, and abnormalities in the eutopic endometrium [5,
7–10]. However, the events that are referred to in these hypotheses
do not occur in isolation during the onset and development of
endometriosis. Regarding the pathogenic mechanism of endometrio-
sis, the etiology of endometriosis is as follows: changes in genetic
traits are present; an abnormal eutopic endometrium is the disease
determinant; immune system abnormalities are prerequisites; and
retrograde menstruation is the bridge between the aforementioned
latent factors. Together, these factors eventually lead to the onset of
endometriosis. Simultaneously, coelomic metaplasia and induction
followed by lymphatic and vascular dissemination are modifications
and supplements to the pathogenesis of endometriosis [1, 7–10].
Ectopic endometrial implantation caused by
retrograde menstruation and the abnormal eutopic
endometrium theory
Currently, the most widely accepted theory of endometriosis is
endometrial ectopic implantation caused by retrograde menstrua-
tion, as proposed by Sampson in 1921. Sampson’s theory proposed
that endometrial glandular epithelial and mesenchymal cells enter
the pelvic cavity by retrograde menstruation and are ectopically
implanted into the ovary and the adjacent pelvic peritoneum, where
they continue to grow and spread to form ectopic lesions. However,
not all women with retrograde menstruation exhibit endometriosis
[11].
Accumulative studies analyzing various processes, namely, gene
expression, proteomics, miRNA expression, hormone sensitivity,
cell differentiation, and related cell signaling pathways, have
revealed that there are significant differences between the eutopic
endometrium of endometriosis patients and that of healthy subjects
[12, 13]. Simultaneously, a group of Chinese scholars, namely,
Y. Liu et al., 2020, Vol. 102, No. 6
Lang et al, also proposed an abnormal eutopic endometrium as the
pathogenesis of endometriosis, which suggests that a fundamental
abnormality in the eutopic endometrium determines whether the
endometrium can adhere, invade, and undergo angiogenesis outside
the uterine cavity; additionally, immune and endocrine factors, as
auxiliary factors, promote the development of endometriosis [14,
15]. The hypothesis of the abnormal eutopic endometrium partly
explains how retrograde menstruation can occur in most women of
childbearing age but leads to endometriosis in only a small number
of women, which is an important supplement to and extension
of the theory of endometrial ectopic implantation caused by
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retrograde menstruation. However, the exact mechanism leading to
the abnormal activity of the eutopic endometrium in endometriosis
patients is not yet clear. Therefore, the discovery of endometrial
stem cells (EnSCs) in the endometrium, menstrual blood, and ectopic
lesions is an important development for the existing hypotheses on
the pathogenesis of endometriosis and provides new targets for the
early diagnosis and treatment of endometriosis [16–18].
Endometrial stem cells
Conventionally, the endometrium undergoes periodic regeneration
and shedding approximately 500 times in healthy women during
their reproductive years, and the endometrium grows by approx-
imately 5–7 mm per menstrual cycle, which strongly suggests the
existence and involvement of stem cells in the periodic regenera-
tion of the endometrium. As early as 2000, research demonstrated
that the stromal and glandular cells isolated from the menstrual
blood of healthy individuals can attach to the mesothelium and
synergistically form endometriotic lesions only 5 days after being
transplanted into nude mice [19]. A subsequent report also indicated
that endometriotic lesions were likely to originate from the shedding
of cells or tissues with stemness properties from the basal layer
during menstruation [20]. Finally, a report in 2004 was the first
to demonstrate the existence of EnSCs with promising clonogenic
ability in the endometrium (endometrial epithelial progenitors and
stromal cells) [21].
Currently, it is well known that EnSCs inhabit the basal
layer of the endometrium, and can be successfully isolated from
endometrial tissues (eutopic endometrium and ectopic lesions of
patients with endometriosis) after treatment with collagenase and
from menstrual blood after density gradient centrifugation or
direct treatment to lyse red blood cells. In addition to exhibiting
high proliferative capacity and multipotency, EnSCs positively
express typical surface markers of mesenchymal stem cells, such
as CD29, CD44, CD73, CD90, and CD105, and are negative for
HLA-DR and hematopoietic cell markers, including CD34 and
CD45 [22–24]. Further morphological, immunophenotyping, and
multipotency examinations have all confirmed that EnSCs meet
the classic definition of mesenchymal stem cells [25]. Meanwhile,
several reports have also demonstrated that EnSCs positively express
embryonic stem cell markers, such as OCT-4, SOX2, and Nanog [24,
25]. In addition, the existence of EnSCs in the endometrium is rather
stable, and menstruation and even menopause have no significant
influence on the existence of EnSCs [26].
With our increasing understanding of the heterogeneity of EnSCs
(including mesenchymal stem cells, endothelial progenitors, and
epithelial progenitors) and different subtypes of EnSCs (constituting
CD146+ , SUSD2+ , ICAM1+ , and ABCG2+ subtypes) [26–29], the
current results demonstrate that human EnSCs ectopically implanted
under the renal capsule of immunodeficient mice can form functional
Function of EnSCs in the pathogenesis of endometriosis, 2020, Vol. 102, No. 6
endometrioid tissues and exhibit a response to exogenous estrogen
stimulation that is similar to that of the typical endometrium;
furthermore, the newly generated humanized blood vessels integrate
into the kidney tissues of mice to form a complete blood circulation
system, and transplantation of a mixed population of EnSCs shows
enhanced endometrial tissue remodeling compared with the trans-
plantation of only a single subtype of EnSCs [28, 30]. Therefore, the
abovementioned data strongly suggest the critical role of EnSCs in
the pathogenesis of endometriosis.
EnSCs and endometriosis
Current data have confirmed that angiogenesis and immune dys-
regulation are important characteristics for the development of
ectopic lesions in patients with endometriosis. Detection of pro-
angiogenic factors and inflammatory factors in peritoneal fluid has
revealed that the levels of vascular endothelial growth factor (VEGF),
epidermal growth factor, hepatocyte growth factor, and angiogenin
in the peritoneal fluid of patients with endometriosis are significantly
upregulated compared with the corresponding levels in the healthy
population, while inhibitors of angiogenesis, such as adiponectin
and IP-10, are downregulated; the degree of downregulation is
positively correlated with endometriosis severity [31, 32]. Simulta-
neously, a large number of studies have shown that the number and
activity of macrophages, neutrophils, T lymphocytes, and natural
killer cells in the abdominal cavity and ectopic lesions of patients
with endometriosis are significantly different from those of these
cell types in healthy populations. Abnormal lymphocytes not only
directly promote the occurrence and development of ectopic lesions
by secreting a large number of bioactive factors (VEGF, IL-6 and IL-
8) but also induce a chronic inflammatory microenvironment in the
abdominal cavity and ectopic lesions, providing favorable conditions
for angiogenesis in ectopic lesions [33–35].
Genetically, familial aggregation in endometriosis patients has
been confirmed [36], and the heritability of endometriosis is approx-
imately 50%, which is estimated based on large studies of twins
[37]. Because of this clear heritability, genome-wide association
studies were performed, and nine previously reported and five novel
loci significantly associated with endometriosis risk were identi-
fied, which all harbor genes that function in sex steroid hormone
pathways [38]; meanwhile, a dozen susceptibility regions were also
reported, but these regions only account for just over 4% of the
heritability [7]. Furthermore, the role of environmental factors,
such as hypoxia [39], chronic inflammation [33], bacterial contam-
ination (lipopolysaccharide) [40], endocrine disrupting chemicals
(metals/trace elements, dioxins, and other persistent organic pollu-
tants, nonpersistent chemicals) [41], and oxidative stress (reactive
oxygen species) [42], have been demonstrated to contribute to and
promote the development of endometriosis. Conclusively, the impor-
tant role of EnSCs in promoting angiogenesis and immunomod-
ulation has also been validated and supported by multiple thera-
peutic studies [25, 43–45], which allow us to reasonably speculate
that EnSCs are likely to induce dysfunctional angiogenesis and
immunomodulation via the above-mentioned changes in genetic
or environmental factors, which can promote ectopic implantation
during retrograde menstruation, resulting in the formation of ectopic
lesions.
Previous reports [46, 47] have confirmed that the activity of
the eutopic endometrium in endometriosis patients is significantly
different from that in the healthy population and that the eutopic
endometrium periodically regenerates from the EnSCs that reside in
1155
the basal layer, suggesting dysfunction in eutopic EnSCs (EnSC-EM-
Eu) in patients with endometriosis compared with healthy popula-
tions (EnSC-Control). As expected, significant differences in mRNA
expression between the EnSC-EM-Eu and EnSC-Control were subse-
quently validated. The EnSC-EM-Eu and their differentiated fibrob-
lasts were all resistant to estrogen and without obvious decidualiza-
tion [48]. Although Chan et al found no significant difference in the
cloning efficiency between the EnSC-EM-Eu and EnSC-Control, the
authors still insisted that there was an undetectable difference in the
activity of these two types of EnSCs [49]. Simultaneously, compared
with healthy individuals, the expression of EnSC markers (Notch-
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1 and Numb) was significantly upregulated in the endometrium of
patients with endometriosis based on a recent comparative analysis
of a large number of cases, and the expression level of Notch-1
and Numb was positively correlated with endometriosis severity in
clinical practice [50].
Furthermore, several laboratories successfully isolated ectopic
EnSCs from the ectopic lesions of patients with endometriosis (EnSC-
EM-Ec) and demonstrated that the in vitro migration, proliferation,
and angiogenic capacities of EnSC-EM-Ec were all significantly
improved compared with those of eutopic EnSCs. The enhanced
invasion and angiogenic abilities of EnSC-EM-Ec in vivo were also
demonstrated after their transplantation into immunodeficient mice
[51, 52]. Additionally, EnSC-EM-Ec exhibit distinct immune pheno-
types from eutopic EnSCs by upregulating the expression of toll-like
receptors, collectin, pro-inflammatory factors, and migration, angio-
genic and other related factors, thereby promoting the migration,
proliferation and invasion abilities of eutopic EnSCs and increasing
the degree of fibrosis in ectopic lesions [53, 54]. Furthermore,
patients with endometriosis have more tissue shedding from the basal
layer during menstruation than do healthy individuals, and EnSC-
EM-Eu also show more chemotaxis to ectopic lesions, which can
enrich EnSCs for the formation of ectopic lesions [20, 55].
Consequently, based on the published data, we reasonably
speculated that the dysfunction of eutopic EnSCs (including the
angiogenesis-promoting and immunomodulatory abilities) might
be a prerequisite for the occurrence of endometriosis, which
directly leads to abnormalities in the eutopic endometrium; we also
hypothesized that retrograde menstrual blood, as a bridge, enables
the dysfunctional eutopic endometrium and EnSCs that become
detached during menstruation to ectopically implant in the ovary,
pelvis, and other locations outside of uterus, and these implanted
cells can further proliferate and differentiate to form ectopic lesions
under stimulation by a specific microenvironment (Figure 1).
Application of EnSCs in endometriosis diagnosis
Current status of the clinical diagnosis
of endometriosis
Because endometriosis is a progressive disease, patients usually expe-
rience a delay from the onset of the first symptoms to the definitive
diagnosis of endometriosis (3–11 years), namely, the endometriosis
diagnostic delay; for patients with dysmenorrhoea starting from
menarche, the time of diagnostic delay is even longer [5, 8]. Thus
far, routine endometriosis diagnostic methods, mainly including
laparoscopic findings of ectopic lesions and pathological biopsy
examinations, as well as assisted laboratory examinations and pelvic
ultrasound or abdominal computed tomography examinations, can
confirm the diagnosis of endometriosis and the severity of the
disease. Nevertheless, the diagnostic delay often results in delayed
1156 Y. Liu et al., 2020, Vol. 102, No. 6

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Figure 1. The hypothesis of this study. Dysfunctional eutopic EnSCs play a critical role in the onset of endometriosis by directly causing eutopic endometrium
abnormalities; subsequently, retrograde menstruation delivers dysfunctional eutopic endometrial tissue and EnSCs that are detached during menstruation to
ectopic sites such as the ovaries and pelvic cavity, where they implant and form ectopic lesions.

treatment, which can cause disease deterioration. Laparoscopy,
which is the gold standard for endometriosis diagnosis, still has
some shortcomings, including trauma, high cost, potential risks
after anesthesia, and visceral tissue and vascular injury; moreover,
laparoscopy may lead to the missed diagnosis of some deep or
invisible lesions, which limits its extensive application in the early
diagnosis and treatment of endometriosis [2, 56].
Generally, with their advantages of being noninvasive and objec-
tive, serological markers are more easily accepted by patients and
gynecologists than laparoscopy, but there is still no effective or
unique serological marker for the early diagnosis of endometriosis
in clinical practice. To date, serum CA125 has been the most widely
used diagnostic indicator for endometriosis in clinical practice, and a
large amount of clinical data have demonstrated that the sensitivity
of the CA125 indicator is positively correlated with the severity
of endometriosis, especially for patients with stages III and IV
endometriosis; however, for some patients with mild endometriosis,
the serum CA125 indicator levels are normal, indicating that serum
CA125 alone is insufficient for the early diagnosis of endometriosis
and that the sensitivity and specificity of serum CA125 as a single
indicator need to be improved [57, 58]. Therefore, CA125 has been
combined with other indicators (including CA199, anti-endometrial
antibodies, aldehyde dehydrogenase 1, prolactin, epididymal pro-
tein 4, related inflammatory factors, and endometrial aromatase)
to address its insufficiency as a single indicator and to improve
the sensitivity and specificity of early endometriosis diagnosis. In
addition, based on data such as serum proteomics, peripheral blood
miRNAs, and urine markers, early endometriosis diagnosis has
been extensively investigated, and several promising indicators have
been identified and tested [59–62]. Although the aforementioned
diagnostic methods have positive effects on the clinical diagnosis
and recurrence of endometriosis, there are still many shortcomings
regarding the early diagnosis and risk prediction of potential patients
with endometriosis.
Potential application of menstrual blood derived
EnSCs in early endometriosis diagnosis
Previous studies [46, 47] have focused on comparative analyses of
the differential expression of related genes and proteins in the eutopic
Function of EnSCs in the pathogenesis of endometriosis, 2020, Vol. 102, No. 6
endometrium of patients with endometriosis, in ectopic lesions and in
the eutopic endometrium of healthy people to elucidate the potential
pathogenesis of endometriosis at the tissue level. However, there are
many types of cells involved in the formation of the endometrium
and ectopic lesions, and these cells are synergistically regulated by a
variety of endocrine and immune signals [33, 63]; moreover, there are
significant variations in the endometrium at different physiological
stages (proliferation, secretion, and menstruation) [64, 65], which
seriously affect the reliability of research results and even result in
conflicting conclusions. Therefore, taking the EnSCs implanted in
eutopic and ectopic lesions as the research object can effectively
reduce the number of complex variables involved in exploring the
pathogenesis of endometriosis at the tissue level and ensure the
validity of the results. At the end of 2007, menstrual blood-derived
stromal/stem cells (MenSCs) were successfully isolated, and their
biological characteristics were consistent with the standards of mes-
enchymal stem cells established by the International Cell Therapy
Association [23, 66]. Our previous findings have directly proven
that MenSCs reside in the deciduous endometrium, which suggests
that MenSCs isolated by non-invasive methods have biological char-
acteristics similar to those of EnSCs [24]. Recently, MenSCs have
received extensive attention in view of their advantages, namely, their
abundance and high proliferative capacity, as well as the ease and
non-invasiveness of MenSC sample collection methods [25, 43–45].
As expected, the application of MenSCs has resulted in satisfactory
therapeutic effects in many animal disease models and clinical studies
[67, 68].
To date, the exploration of differences between EnSC-EM-Eu and
EnSC-Control is still in the preliminary stage. However, published
data have confirmed that cell detachment in the basal layer of the
endometrium during menstruation is significantly higher in patients
with endometriosis than in healthy individuals and that the detached
cells involved in retrograde menstruation are likely to provide a
sufficient cell source for the formation of potential ectopic lesions
[20]. Furthermore, significant morphological differences have been
observed between MenSCs isolated from patients with endometrio-
sis and those isolated from healthy individuals; compared with
the MenSCs of healthy individuals, the MenSCs of endometriosis
patients had CD9, CD10, and CD29 expression levels that were
significantly upregulated, proliferation and invasion capacities that
were significantly enhanced, and an immunomodulation ability that
was significantly downregulated [69].
Thus, based on the above results, we contend that MenSCs can be
used as a promising target and that further investigation of the dif-
ferences in the biological characteristics of MenSCs between patients
with endometriosis and healthy individuals should be performed to
screen potential biomarkers (genes or proteins) that underlie the
differences between the MenSCs mentioned above. Simultaneously,
technological development (high-throughput sequencing and protein
assays) can promote and optimize the combination of these poten-
tial biomarkers, which are promising for use as early noninvasive
endometriosis diagnostic strategies. Additionally, with expansion of
the sample size, the diagnostic parameters can be gradually improved
and optimized.
Conclusion
In summary, the in-depth study of EnSCs can improve the stem cell
theory regarding the pathogenesis of endometriosis, partly explain-
ing the onset and development of ectopic lesions at the cellu-
lar level and providing supplements for the existing pathogene-
sis of endometriosis. Furthermore, early noninvasive endometriosis
1157
diagnostic strategies based on MenSCs can be used to improve early
detection and risk evaluations of potential patients with endometrio-
sis, and early interventions can be initiated to prevent or slow disease
progression.
Conflict of Interests
The authors declare that there is no conflict of interest regarding the
publication of this paper.
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