Endometrial Stem Cells: MenSC and Endometriosis Research

• Menstrual blood-derived stem cells (MenSC) are being researched to manage endometriosis, a complex disease.

Endometrial Stem Cells

• Stem cells renew themselves and differentiate, responsible for development, regeneration, and renewal of organs/tissues.
• The human endometrium has two regions:
  • Functionalis: Upper two-thirds, sheds during menstruation.
  • Basalis: Lower third, remains unchanged.
• Prianishnikov proposed in 1978 that cyclic regeneration is mediated by resident adult stem cell populations.
• There are three kinds of stem cells in the human endometrium:
  • Epithelial Stem Cells: Specific markers under investigation
  • Mesenchymal Stem Cells: CD140 + CD146b + eMSC, CD29, CD44, CD73, CD90 and CD105 markers, and SUSD2.
  • Endothelial Stem Cells: SP cells and CD31, CD34 and CD54, EMA, CD90, CD105 and CD146 markers
• CD140b + CD146 + eMSC exhibit perivascular localization, differentiate into various lineages, and express genes for angiogenesis, inflammation, and immunomodulation.
• SUSD2+ cells reside in the perivascular region and differentiate into adipocytes, osteocytes, chondrocytes, myocytes, and endothelial cells.
• SP cells differentiate gland and stromal-like cells, found in both endometrial layers and are mostly quiescent.

Stem Cell Theory for Endometriosis Pathogenesis

• Sampson proposed in 1921 implantation caused by retrograde menstruation is the most accepted theory for endometriosis.
• Endometrial glandular epithelial and mesenchymal cells enter the pelvic cavity via retrograde menstruation and implant in ectopic sites, growing into lesions.
• The initial stem cell theory suggests endometriotic lesions arise from stem cells that translocate into ectopic sites and differentiate into glandular, stromal, endothelial, and smooth muscle cells.
• Menstrual stage eMSC undergo more rounds of self-renewal than proliferative/secretory stage eMSC, highlighting their potential as lesion-initiating cells.

Menstrual-Blood Derived Stem Cells

• MenSC are derived from menstrual blood.
• MenSC mainly express CD29, CD9, CD13, CD44, CD41a, CD73, CD59, CD90 and CD105 but not CD19, CD34, CD45, CD117, CD130 or HLA-DR.
• MenSC were first identified in 2007.
• Recent studies show MenSC double every 20 h with sufficient culture conditions, almost twice as fast as BM-MSC.
• MenSC have an extra broad differentiation capacity into adipocytic, osteogenic, cardiomyocytic and neuronal lineages, as well as respiratory epithelial, endothelial, myocytic, hepatic, germ-like and pancreatic cells.
• The expression of MHC-I indicates MenSC's immunomodulation capability.
• MenSC also inhibit the optimal phenotypic differentiation of human PBMC into immature and mature DC.
• Studies also revealed that menstrual blood is a source of MenSC and DC to form an innate sensing of pathogens.

MenSC in Patients with Endometriosis vs. Patients without Endometriosis

• E-MenSC display different morphologic, phenotypic, and functional characteristics when compared to NE-MenSC.
• NE-MenSC have a characteristic fibroblast-like spindle shape, whereas E-MenSC are described as being less stretched and elongated.
• E-MenSC form small colonies when grown in 3D cultures, which are absent in NE-MenSC cultures.
• E-MenSC and NE-MenSC were considered positive for CD9, CD10 and CD29, although their expression was significantly higher in E-MenSC that in NE-MenSC.
• E-MenSC possess higher proliferation and invasion capacities, higher migratory capacity, lower apoptosis, high VEGF expression, and increased stemness-related markers.
• Genes such as ATF3, ID1, ID3, FOSB, SNAI1, NR4A1, EGR1, LAMC3, and ZFP36 and the proteins COL1A1, COL6A2, and NID2 were considered to be overexpressed in E-MenSC when compared to NE-MenSC.

MenSC-Based Early Diagnosis

• Patients with endometriosis often experience a delay from the onset of symptoms to a definitive diagnosis, which can be up to 11 years.
• Findings pave the way for novel multi-omics approaches to evaluate differences in MenSC between healthy individuals and patients with endometriosis.
• MenSC might also be helpful in predicting the risk of developing endometriosis in the future for healthy women.
• Cousins et al. suggested early diagnosis via neonatal uterine bleeding (NUB).
• Fetal endometrial stem cells invade the mesothelium and remain dormant until puberty.

MenSC-Based Therapies

• MenSC-based therapies mainly relate to the regular and non-invasive way that these cells can be obtained from menstrual blood.
• MenSC exhibit the ability to migrate into injury sites, differentiate into distinct cell lineages, secrete soluble factors, and regulate immune responses, much like bone marrow mesenchymal stem cells
• Sahraei et al. and Nikoo et al. highlight the presumed role of MenSC in improving endometriosis.
• Menstrual blood sample collection and MenSC isolation must be performed under aseptic conditions in agreement with the good manufacturing practice standards.

Conclusions

• MenSC are attractive cells to study mainly due to their proliferation, differentiation, and immunomodulatory characteristics, in association with the regular and non-invasive way they can be obtained.
• The differences found between MenSC from patients with endometriosis and those without endometriosis pave the way to the identification of biomarkers for early diagnosis and the development of targeted therapies.
• After the safety and effectiveness of MenSC is proven in endometriosis treatment, these cells will have the relevant potential to change the way the disease is managed.