*4.2. Endometrial Stem Cells in Pathogenesis of Endometrial Pathology*

There are several theories to account for the origin of endometriosis and to explain how tissue can be scattered throughout the abdominal cavity. However, there is no single theory that can explain all clinical presentations and pathological features observed in endometriosis, and several mechanisms may in fact contribute.

The stem cell origin theory of endometriosis has gained considerable attention in recent years following the advances in molecular and genetic findings. There are two main models that are differentiated based on the tissue origin of the stem cells: stem cells arising from the regenerating uterine endometrium or stem cells originating from the bone marrow. The uterus in women is the only organ that undergoes repeated cycles of physiological damage, repair, and regeneration following menstrual shedding [114–116]. Menstrual shedding, and the subsequent repair of the endometrial functionalis, is a process unique to humans and higher-order primates [117–119]. These approximately 400 cycles of shedding and regeneration occur over a woman's lifetime. This significant regenerative capacity is thought to be driven by stem cells that reside in the terminal ends of the basalis glands at the endometrial/myometrial interface, also termed endometrial functionalis layer, which persists after menstruation and regenerates the epithelium during the proliferative phase in response to estrogen [9]. The first model proposes that circulating epithelial progenitor or stem cells intended to regenerate the uterine endometrium are shed with menstruation and may become aberrantly activated and trapped outside the uterus, thus giving rise to ectopic lesions after retrograde menstruation and trans-tubal migration in to the pelvic cavity [157].

Irrespective of the site of stem cell origin, the growth of the ectopic tissue, which retains hormone responsiveness, is further influenced by sex hormones and other factors present in the microenvironment. These factors collectively control the adhesion, proliferation, angiogenesis, and invasion of the trapped progenitor cells. The ectopic tissue, in turn, induces the recruitment of immune cells leading to local inflammation and the formation of a dysregulated inflammation–hormonal autoregulatory loop. The trapped progenitor cells thereby may form nascent glands in the epithelium through clonal expansion leading to the establishment of deep infiltrating endometriosis.

However, more studies for a better understanding of endometrial epithelial stem cell function and regulation are required to understand the eventual changes behind the endometrial pathologies.
