Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions

The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This massive regenerative capacity is thought to have a stem cell basis, with human endometrial stromal stem cells having already been extensively studied. Studies on endometrial epithelial stem cells are sparse, and the current belief is that the endometrial epithelial stem cells reside in the terminal ends of the basalis glands at the endometrial/myometrial interface. Since almost all endometrial pathologies are thought to originate from aberrations in stem cells that regularly regenerate the functionalis layer, expansion of our current understanding of stem cells is necessary in order for curative treatment strategies to be developed. This review critically appraises the postulated markers in order to identify endometrial stem cells. It also examines the current evidence supporting the existence of epithelial stem cells in the human endometrium that are likely to be involved both in glandular regeneration and in the pathogenesis of endometrial proliferative diseases such as endometriosis and endometrial cancer.

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Distribution of amniotic stem cells in human term amnion membrane

Microscopy ◽

10.1093/jmicro/dfab035 ◽

2021 ◽

Author(s):

Nobuyuki Koike ◽

Jun Sugimoto ◽

Motonori Okabe ◽

Kenichi Arai ◽

Makiko Nogami ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Markers ◽

Epithelial Stem Cells ◽

Human Amnion ◽

Transporter Protein ◽

Amniotic Mesenchymal Stem Cells ◽

Amnion Membrane ◽

And Function ◽

A Site

Abstract Amnion membrane studies related to miscarriage have been conducted in the field of obstetrics and gynecology. However, the distribution of stem cells within the amnion and the differences in the properties of each type of stem cells are still not well understood. We address this gap in knowledge in the present study where we morphologically classified the amnion membrane, and we clarified the distribution of stem cells here to identify functionally different amniotic membrane–derived stem cells. The amnion can be divided into a site that is continuous with the umbilical cord (region A), a site that adheres to the placenta (region B), and a site that is located opposite the placenta (region C). We found that human amnion epithelial stem cells (HAECs) that strongly express stem cell markers were abundant in area A. HAEC not only expressesed stem cell-specific surface markers TRA-1-60, Tra-1-81, SSEA4, SSEA3, but was also OCT-3/4 positive and had alkaline phosphatase activity. Human amniotic mesenchymal stem cells expressed KLF-A, OCTA, Oct3/4, c-MYC and Sox2 which is transcription factor. Especially, in regions A and B they have expressed CD73, and the higher expression of BCRP which is drug excretion transporter protein than the other parts. These data suggest that different types of stem cells may have existed in different area. The understanding the relation with characteristics of the stem cells in each area and function would allow for the efficient harvest of suitable HAE and HAM stem cells as using tool for regenerative medicine.

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Derivation and Characterization of EGFP-Labeled Rabbit Limbal Mesenchymal Stem Cells and Their Potential for Research in Regenerative Ophthalmology

Biomedicines ◽

10.3390/biomedicines9091134 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1134

Author(s):

Julia I. Khorolskaya ◽

Daria A. Perepletchikova ◽

Daniel V. Kachkin ◽

Kirill E. Zhurenkov ◽

Elga I. Alexander-Sinkler ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Fluorescent Protein ◽

Rabbit Model ◽

Stem Cell Markers ◽

Epithelial Stem Cells ◽

Limbal Stem Cell ◽

Green Fluorescent

The development of cell-based approaches to the treatment of various cornea pathologies, including limbal stem cell deficiency (LSCD), is an area of current interest in regenerative biomedicine. In this context, the shortage of donor material is urgent, and limbal mesenchymal stem cells (L-MSCs) may become a promising cell source for the development of these novel approaches, being established mainly within the rabbit model. In this study, we obtained and characterized rabbit L-MSCs and modified them with lentiviral transduction to express the green fluorescent protein EGFP (L-MSCs-EGFP). L-MSCs and L-MSCs-EGFP express not only stem cell markers specific for mesenchymal stem cells but also ABCG2, ABCB5, ALDH3A1, PAX6, and p63a specific for limbal epithelial stem cells (LESCs), as well as various cytokeratins (3/12, 15, 19). L-MSCs-EGFP have been proven to differentiate into adipogenic, osteogenic, and chondrogenic directions, as well as to transdifferentiate into epithelial cells. The possibility of using L-MSCs-EGFP to study the biocompatibility of various scaffolds developed to treat corneal pathologies was demonstrated. L-MSCs-EGFP may become a useful tool for studying regenerative processes occurring during the treatment of various corneal pathologies, including LSCD, with the use of cell-based technologies.

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Islet morphogenesis and stem cell markers in rat pancreas.

Journal of Histochemistry & Cytochemistry ◽

10.1177/44.9.8773559 ◽

1996 ◽

Vol 44 (9) ◽

pp. 947-951 ◽

Cited By ~ 69

Author(s):

L Bouwens ◽

E De Blay

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Epithelial Cells ◽

Endocrine Cells ◽

Stem Cell Marker ◽

Intermediate Filament Protein ◽

Stem Cell Markers ◽

Epithelial Stem Cells ◽

Duct Cells ◽

Pancreatic Islets Of Langerhans

During embryonic development, and possibly also later in life, pancreatic islets of Langerhans originate from differentiating epithelial stem cells. These stem cells are situated in the pancreatic ducts but are otherwise poorly characterized. We found by immunohistochemical staining that protodifferentiated pancreatic epithelial cells from rat embryos of Day 13-Day 15 express the cytoskeletal protein keratin 20, similar to mature duct epithelium. During the period of islet morphogenesis, which occurs between Day 17 and birth, large aggregates of K20-positive duct cells were formed, which gradually differentiated into endocrine cells. This islet morphogenic mechanism has not been described thus far and we did not observe it in postnatal rats. During fetal islet formation, transient expression of vimentin was noted in the duct cells but not in endocrine cells. This intermediate filament protein is not observed in duct epithelial cells after birth. The proto-oncogene product bcl-2, a putative epithelial stem cell marker, was detected in duct cells from fetal and postnatal pancreas. We conclude that K20, vimentin, and bcl-2 are markets for the pancreatic (islet) stem cells.

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LRIG1 is a positive prognostic marker in Merkel cell carcinoma and Merkel cell carcinoma expresses epithelial stem cell markers

Virchows Archiv ◽

10.1007/s00428-021-03158-7 ◽

2021 ◽

Author(s):

Benjamin Sundqvist ◽

Harri Sihto ◽

Maria von Willebrand ◽

Tom Böhling ◽

Virve Koljonen

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Stem Cell Markers ◽

Merkel Cell ◽

Epithelial Stem Cells ◽

Normal Human Skin ◽

Cell Markers ◽

Normal Human

AbstractMerkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine malignancy of the skin. The cell of origin of MCC is thus far unknown and proposed cells of origin include Merkel cells, pro-/pre- or pre-B cells, epithelial stem cells, and dermal stem cells. In this study, we aimed to shed further light on the possibility that a subset of MCC tumors arise from epithelial stem cells of the skin by examining the expression of hair follicle and epidermal stem cell markers in MCC and normal human skin. We also aimed to elucidate any correlation between the expression of these markers and tumor Merkel cell polyomavirus (MCPyV) status or other clinicopathological characteristics or patient survival. Expression of CK19, SOX9, LGR5, and LRIG1 in MCC and normal human skin was studied by immunohistochemistry, and the staining patterns or intensities were statistically correlated with patient, tumor, MCPyV, and survival parameters. In a cohort of 137 cases of MCC, we observed dot-like immunoexpression of CK19 in 30 cases (22.1%) and homogeneous expression in 103 cases (75.7%). We also observed positive immunoexpression of SOX9 in 21 cases (15.3%), LGR5 in 118 cases (86.1%), and LRIG1 in 117 cases (86.0%). Immunoexpression of LRIG1 was found to correlate with better overall and MCC-specific survival. We observed frequent immunoexpression of several hair follicle and epidermal stem cell markers in MCC and found LRIG1 to be a positive prognostic marker in MCC.

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003. ENDOMETRIUM: CINDERELLA TISSUE IN A STEM CELL WORLD

Reproduction Fertility and Development ◽

10.1071/srb09abs003 ◽

2009 ◽

Vol 21 (9) ◽

pp. 3

Author(s):

C. E. Gargett

Keyword(s):

Stem Cells ◽

Endometrial Cancer ◽

Stem Cell ◽

Epithelial Cells ◽

Progenitor Cells ◽

Stromal Cells ◽

Human Endometrium ◽

Cancer Tissue ◽

Stem Cell Markers ◽

Epithelial Progenitor Cells

Despite human endometrium undergoing more than 400 cycles of regeneration, differentiation and shedding during a woman's reproductive years, and that in non-menstruating species (eg rodents) there are cycles of endometrial growth and apoptosis, endometrial stem/progenitor cells have only recently been identified. Since there are no specific stem cell markers, initial studies using functional approaches identified candidate epithelial and stromal endometrial stem/progenitor cells as colony forming cells/units (CFU) (1). Further evaluation of key stem cell properties of individual CFU demonstrated that rare EpCAM+ epithelial cells and EpCAM- stromal cells underwent self renewal by serial subcloning >3 times and underwent >30 population doublings in culture. Clonally-derived epithelial cells differentiated into cytokeratin+ gland-like structures. Single stromal cells were multipotent as they differentiated into 4 mesodermal lineages; myogenic, adipogenic, osteoblastic and chondrogenic, suggesting that human endometrium contains a rare population of epithelial progenitor cells and mesenchymal stem cells (MSC) (2). Transplantation of freshly isolated human endometrial cells into immunocompromised mice reconstructed endometrial tissue that responded to estrogen and progesterone (3). Endometrial MSC can be prospectively isolated by co-expression of CD146 and PDGFRβ (4), but not Stro-1, a bone marrow MSC marker (5). Currently there are no known markers of endometrial epithelial progenitor cells. Endometrial cancer tissue harbours a small subpopulation of clonogenic, self-renewing, tumour-initiating cells, producing tumours that recapitulate parent tumours in histoarchitecture and differentiation markers (ERα, PR, cytokeratin, vimentin) when xenografted into mice, suggesting they are cancer stem cells. Candidate epithelial and stromal stem/progenitor cells have been identified in mouse endometrium as label retaining cells (LRC) in the luminal epithelium and perivascular cells at the endometrial-myometrial junction, respectively (6). It is likely that endometrial stem/progenitor cells play key roles in the development of gynecological diseases associated with abnormal endometrial proliferation such as endometriosis and endometrial cancer (7).

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Corneal Stem Cells as a Source of Regenerative Cell-Based Therapy

Stem Cells International ◽

10.1155/2020/8813447 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Jasmin S. Nurković ◽

Radiša Vojinović ◽

Zana Dolićanin

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Therapeutic Potential ◽

Corneal Stroma ◽

Epithelial Stem Cells ◽

Corneal Surface ◽

Cell Based Therapy ◽

Corneal Regeneration ◽

Successful Transplantation ◽

Stromal Stem Cells

In the past few years, intensive research has focused on corneal stem cells as an unlimited source for cell-based therapy in regenerative ophthalmology. Today, it is known that the cornea has at least two types of stem cells: limbal epithelial stem cells (LESCs) and corneal stromal stem cells (CSSCs). LESCs are used for regeneration of corneal surface, while CSSCs are used for regeneration of corneal stroma. Until now, various approaches and methods for isolation of LESCs and CSSCs and their successful transplantation have been described and tested in several preclinical studies and clinical trials. This review describes in detail phenotypic characteristics of LESCs and CSSCs and discusses their therapeutic potential in corneal regeneration. Since efficient and safe corneal stem cell-based therapy is still a challenging issue that requires continuous cooperation between researchers, clinicians, and patients, this review addresses the important limitations and suggests possible strategies for improvement of corneal stem cell-based therapy.

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“Empowering” Cardiac Cells via Stem Cell Derived Mitochondrial Transplantation- Does Age Matter?

International Journal of Molecular Sciences ◽

10.3390/ijms22041824 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1824

Author(s):

Matthias Mietsch ◽

Rabea Hinkel

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Treatment Strategies ◽

Cardiac Cells ◽

Aging Effects ◽

Beneficial Effects ◽

Micro Rnas ◽

New Treatment

With cardiovascular diseases affecting millions of patients, new treatment strategies are urgently needed. The use of stem cell based approaches has been investigated during the last decades and promising effects have been achieved. However, the beneficial effect of stem cells has been found to being partly due to paracrine functions by alterations of their microenvironment and so an interesting field of research, the “stem- less” approaches has emerged over the last years using or altering the microenvironment, for example, via deletion of senescent cells, application of micro RNAs or by modifying the cellular energy metabolism via targeting mitochondria. Using autologous muscle-derived mitochondria for transplantations into the affected tissues has resulted in promising reports of improvements of cardiac functions in vitro and in vivo. However, since the targeted treatment group represents mainly elderly or otherwise sick patients, it is unclear whether and to what extent autologous mitochondria would exert their beneficial effects in these cases. Stem cells might represent better sources for mitochondria and could enhance the effect of mitochondrial transplantations. Therefore in this review we aim to provide an overview on aging effects of stem cells and mitochondria which might be important for mitochondrial transplantation and to give an overview on the current state in this field together with considerations worthwhile for further investigations.

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Stem Cells in the Path of Light, from Corneal to Retinal Reconstruction

Biomedicines ◽

10.3390/biomedicines9080873 ◽

2021 ◽

Vol 9 (8) ◽

pp. 873

Author(s):

Ovidiu Samoila ◽

Lacramioara Samoila

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Clinical Success ◽

Corneal Stroma ◽

Cell Transplant ◽

Inclusion Criteria ◽

Epithelial Stem Cells ◽

Corneal Epithelial ◽

Stem Cells Transplantation ◽

Limbal Epithelial Stem Cells

The future of eye reconstruction invariably includes stem cells transplantation. Corneal limbus, corneal stroma, trabeculum, retinal cells, optic nerve, and all structures that are irreversibly damaged and have no means to be repaired or replaced, through conventional treatment or surgery, represent targets for stem cell reconstruction. This review tries to answer the question if there is any clinical validation for stem therapies, so far, starting from the cornea and, on the path of light, arriving to the retina. The investigation covers the last 10 years of publications. From 2385 published sources, we found 56 clinical studies matching inclusion criteria, 39 involving cornea, and 17 involving retina. So far, corneal epithelial reconstruction seems well validated clinically. Enough clinical data are collected to allow some form of standardization for the stem cell transplant procedures. Cultivated limbal epithelial stem cells (CLET), simple limbal epithelial transplant (SLET), and oral mucosa transplantation are implemented worldwide. In comparison, far less patients are investigated in retinal stem reconstructions, with lower anatomical and clinical success, so far. Intravitreal, subretinal, and suprachoroidal approach for retinal stem therapies face specific challenges.

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Stress resistant human embryonic stem cells as a potential source for the identification of novel cancer stem cell markers

Cancer Letters ◽

10.1016/j.canlet.2009.08.018 ◽

2010 ◽

Vol 289 (2) ◽

pp. 208-216 ◽

Cited By ~ 4

Author(s):

Shaker A. Mousa ◽

Thangirala Sudha ◽

Evgeny Dyskin ◽

Usawadee Dier ◽

Christine Gallati ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Embryonic Stem Cells ◽

Cancer Stem Cell ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Stem Cell Markers ◽

Cell Markers ◽

Cancer Stem Cell Markers ◽

Potential Source

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Ovarian Epithelial Cancer Stem Cells

The Scientific World JOURNAL ◽

10.1100/tsw.2011.112 ◽

2011 ◽

Vol 11 ◽

pp. 1243-1269 ◽

Cited By ~ 10

Author(s):

Irena Conic ◽

Irena Dimov ◽

Desanka Tasic-Dimov ◽

Biljana Djordjevic ◽

Vladisav Stefanovic

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Potential Role ◽

Research Field ◽

Current Evidence ◽

Epithelial Stem Cells ◽

Ovarian Epithelial Cancer ◽

Cells Of Origin ◽

Cancer Types ◽

And Function

The last decade witnessed an explosion of interest in cancer stem cells (CSCs). The realization of epithelial ovarian cancer (EOC) as a CSC-related disease has the potential to change approaches in the treatment of this devastating disease dramatically. The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies. Compared to the CSCs of other cancer types, the identification and study of EOC stem cells (EOCSCs) is rather difficult due to several major obstacles: the heterogeneity of tumors comprising EOCs, unknown cells of origin, and lack of knowledge considering the normal ovarian stem cells. This poses a major challenge for urgent development in this research field. This review summarizes and evaluates the current evidence for the existence of candidate normal ovarian epithelial stem cells as well as EOCSCs, emphasizing the requirement for a more definitive laboratory approach for the isolation, identification, and enrichment of EOCSCs. The present review also revisits the ongoing debate regarding other cells and tissues of origin of EOCs, and discusses early events in the pathogenesis of this disease. Finally, this review discusses the signaling pathways that are important regulators of candidate EOCSC maintenance and function, their potential role in the distinct pathogenesis of different EOC subtypes, as well as potential mechanisms and clinical relevance of EOCSC involvement in drug resistance.

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