The endometrium as a source of mesenchymal stem cells in domestic animals and possible applications in veterinary medicine

The endometrium as a source
of mesenchymal stem cells
in domestic animals and possible
applications in veterinary medicine

 

Ana G.Serrato López1,2

0000-0002-7684-9356

Juan J. Montesinos Montesinos2

0000-0002-1042-3205

Santiago R. Anzaldúa Arce1*

0000-0002-1034-9551


1 Departamento de Morfología.
Facultad de Medicina Veterinaria y Zootecnia.
Universidad Nacional Autónoma de México.
Avenida Universidad #3000, Delegación Coyoacán, D.F
CP 04510, Mexico City, Mexico.

2 Laboratorio de Células Troncales Mesenquimales,
Unidad de Investigación Médica
en Enfermedades Oncológicas,
Centro Médico Nacional Siglo XXI, IMSS,
Ciudad de México, México. C.P. 6720.


*Corresponding author:

Tel and fax: + 52 55 5622 5893

Email address: reneanzalduaarce@yahoo.com.mx


Received: 2017-02-17

Accepted: 2017-08-24

Published: 2017-09-04


DOI: http://dx.doi.org/10.21753/vmoa.4.3.441


Additional information and declarations here

Copyright 2017 Ana G.Serrato López et al.

open access

Conjugated linoleic acid supplementation does not improve boar semen quality and does not change its fatty acid profile Distributed under Creative Commons CC-BY 4.0

 

Abstract

Mesenchymal stem cells (MSCs) have been isolated from the endometrium of humans, mice, cows, pigs and ewes. Typically, these cells are detected in the deep regions of the endometrium, closer to the union with the myometrium. MSCs possess characteristics such as clonogenicity and multipotentiality since they can differentiate in vitro into adipogenic, chondrogenic and osteogenic lineages. These cells can be induced to differentiate in vitro not only into the mesodermal lineage but also into the endodermal and ectodermal lineages. Therefore, MSCs show a great regenerative capacity for various organs and tissues, including the endometrium. Some advantages of endometrial MSCs compared with other MSC sources are their immune modulating activity, their ease of obtainment, and the amount of sample that may be collected. The study of endometrial MSCs in domestic animals is a new and promising field because increasing our understanding of the physiology and biology of these cells may lead to a better understanding of the physiopathology of reproductive diseases, and the development of treatment methods for infertility problems. In other veterinary medicine fields, MSCs can be used for the treatment of autoimmune diseases, cardiac affections, musculoskeletal and articular lesions, muscle degeneration, type 1 diabetes, urinary tract diseases, neurodegenerative processes and tumours. Finally, MSCs are also an important clinical tool for tissue engineering and regenerative medicine. The aim of this review is to present an updated outlook of the knowledge regarding endometrial MSCs and their possible applications in veterinary medicine.

Keywords: Uterus, mesenchymal stem cells, regenerative medicine, immune modulation, veterinary medicine.

Introduction

The uterus is an organ with a remarkable capacity for cyclic renovation throughout the reproductive life of females. The human endometrium is formed of a functional layer and a basal layer and goes through approximately 400 cycles of proliferation, differentiation and detachment during a woman’s reproductive life.1 During each menstrual cycle, approximately 4 to 7 mm of tissue is regenerated during the proliferative phase.2 Species that have an oestrous cycle include cycles of endometrial growth and cell apoptosis. Endometrial renovation in every mammal is regulated by oestrogen and progesterone secretion.1-3 The level of endometrial tissue regeneration is similar to that of tissues where the existence of stem cells has been demonstrated, such as the intestinal epithelium, epidermis and bone marrow (BM).4

The hypothesis that endometrial regeneration (particularly in humans) was mediated by stem cells was postulated many years ago.5 Over 70 years ago, the first indications of a stem/progenitor cell presence in the uteri of rhesus monkeys was published; complete regeneration of the uterus was observed after an almost total resection of the endometrium.6 Clinical cases have also reported endometrial renovation in women even after resection that can support gestation.7-9 Bone and cartilaginous tissues have been found in the endometrium,10-12 suggesting the presence of mesenchymal stem cells (MSCs). Despite the aforementioned findings, the first evidence for the presence of MSCs in the human endometrium based on functional testing was relatively recent.13

MSCs are a cell population that can be differentiated in vitro into various cell lineages, including osteogenic, chondrogenic, adipogenic, myogenic, tenogenic and stromal cells.14-16 These differentiations can be identified using staining, such as oil red O (for lipid vesicles), alizarin crimson (for osteogenesis), von Kossa (for calcified extracellular matrices) or alcian blue (for sulfated proteoglycans).17 The Mesenchymal and Stem Cell Tissue Committee of the International Society for Cellular Therapy proposed the following criteria to define human MSCs18: (1) MSCs adhere to the culture tray when maintained under standard conditions and form fibroblast colony-forming units (CFU-Fs); (2) MSCs express the CD105, CD73 and CD90 markers but do not express the CD45, CD34, CD14 or CD11b, CD79 alpha or CD19, and HLA-DR surface molecules; and (3) MSCs can be differentiated in vitro into osteoblasts, adipocytes and chondroblasts.

MSCs have been found in foetal blood, amniotic fluid, the placenta, and the umbilical cord. In adults, MSCs are resident cells in the BM and in many other organs and tissues, including adipose tissue, the dermis, intervertebral discs, teeth, peripheral blood,14,16 and the endometrium.1 As a prominent tool in regenerative medicine, cellular therapy is a strategy that consists of substituting damaged cells or tissues with the aim of restoring their altered functions following provocation by different causes, including disease, congenital malformations and trauma. Generally, MSCs possess the following four relevant biological properties that allow them to be considered an option for cellular therapy: (1) a high capacity for cellular differentiation into different cell types (plasticity); (2) low immunogenicity; (3) an ability to secrete various factors that are responsible for tissue renovation; and (4) an immune regulation capacity (or immunomodulation ability).19

An advantage of the endometrium compared with other MSC sources is the accessibility of MSCs and the amount of sample that can be collected. In domestic animals, these cells can be obtained through hysterectomy, with the advantage of removing the entire organ containing these cells instead of a small sample. In humans, MSCs can be obtained through an endometrial biopsy, which is a procedure that does not require anaesthesia and is less invasive and less painful than a marrow aspiration or liposuction.20 Therefore, the endometrium can be considered a good MSC source. The aim of this review is to present an updated outlook of the knowledge regarding endometrial MSCs and their possible applications in veterinary medicine.

Endometrial origin of MSCs

The female reproductive system originates from the intermediate mesoderm. Some cells are thought to undergo a transition from the mesenchymal to epithelial lineage as the tissue proliferates to form a coelomic epithelium, which will subsequently invaginate to form paramesonephric or Müller ducts.21 One hypothesis regarding the origin of endometrial MSCs is that a few epithelial cells and MSCs remain in the adult endometrium.22

A second possible origin for endometrial MSCs is the BM. BM-MSCs have been reported to circulate in small numbers and can be established in other organs,23 where they perform a transdifferentiation process to originate into cells of the new tissue or contribute to angiogenesis.24 To prove this hypothesis, some BM-MSC screening assays have been conducted using cells grafted into women through transplants. Significant chimaerism was detected in one of these assays in 0.2 to 52 % of the glands and in the endometrial stroma of women who received a BM transplant, suggesting that the BM-MSCs contributed to endometrial regeneration.25 However, another study in which women were transplanted with male donor bone marrow suggested that endometrial cells were more likely to be produced by the resident endometrial stem cells,26 which are responsible for uterus regeneration, although small amounts of endometrial cells were found in the recipients’ endometria.27

Endometrium stem cell phenotype

Cultured endometrial MSCs usually express typical BM-MSC markers, such as CD90, CD105, CD14628, CD9, CD13, CD14, CD29, CD31, CD44, CD73, CD117 and CD13318, but they do not express other markers, such as STRO 1, CD31 (typical of endothelial origin cells), or CD34, from haematopoietic stem cells (HSCs) and endothelial cells.29

General adult stem cell markers, such as bcl-2, c-kit (CD117) and CD34, have been identified in human endometrial tissue.30 Additionally, Oct-4 has been reported to be expressed in almost half of the analyzed human endometrial samples.31 Sporadic expression of the NANOG and SOX 2 pluripotency-associated genes has also been reported in the endometrial stromal cells of pigs.32

Using flow cytometry analysis, cells with a HSC (CD34 and CD45) phenotype and co-expression of the CD7 and CD56 markers (which appear to be lymphoid precursors) have been identified in human endometrial suspensions33; this finding may be due to the presence of small numbers of haematopoietic stem cells in the samples.

Cells originating from menstrual secretions express the CD9, CD29, CD41a, CD44, CD59, CD73, CD90 and CD105 markers.34 Endometrial MSCs have also been purified based on the co-expression of two perivascular markers (CD140b and CD146).35 Masuda et al.36 found that the W5C5 (SUSD2) perivascular protein was a marker that could be used for human endometrial MSCs. Finally, Ishikawa et al.37 demonstrated that NAC1, which was a transcriptional repressor that was implicated in the auto-renovation and maintenance of pluripotentiality in embryonic stem cells,38 was over-expressed during the proliferative phase of the normal endometrial menstrual cycle.

Endometrial MSCs in humans

The first evidence for the existence of stem cells in the human endometrium was presented by Dr. Caroline Gargett and her research group,13 who analyzed endometrial tissues obtained from women undergoing a hysterectomy. They purified and cultured the cells and found that a small number of isolated cells could form individual colonies.13 This result indicated that the cells exhibited clonogenicity and a high proliferation capacity, both of which are stem cell characteristics. These isolated cells showed MSC features, because they were able to differentiate into the adipogenic, chondrogenic, osteogenic and smooth muscle lineages.39

MSCs obtained from the human endometrium have been demonstrated in vitro to have a better capacity to differentiate into mesoderm lineages than cells obtained from adipose tissue. Moreover, endometrial MSCs are able to differentiate not only into the osteogenic, chondrogenic and adipogenic lineages but also show an apparent plasticity since they are capable of differentiating into cardiomyocytes, respiratory epithelial cells, neuronal cells, pancreatic cells and hepatic cells.34,40 Furthermore, the possible use of these cells in the treatment of myocardial infarction has been suggested due to their angiogenic capacity.41

The ability of human endometrial MSCs to regenerate tissue has been demonstrated in experimental models with xenografts. Transplant of purified suspensions of human endometrial MSCs under the renal capsule of NOG mice, which lack T and B lymphocytes and NK cells, has achieved the generation of endometrial,42,43 and myometrial tissue layers in the uterus.44

Stem cells use an ABC transporter (ATP binding cassette) in their cellular membrane to eliminate toxins. Therefore, proteins of the ABC superfamily may be used as markers to identify and characterize stem cells based on the elimination of the Hoechst 33342 vital DNA dye from the cytoplasm by these transporters. This elimination process may be visualized using flow cytometry, resulting in side population cells.45 Based on verapamil inhibition studies, two proteins of the ABC superfamily can be considered responsible for active transport in stem cells: ABCB1 (also known as MDR1) and ABCG2.46,47 The phenotype of these side population cells has been suggested to be a universal marker for adult stem cell activity.48

In vivo assays have demonstrated that endometrial side population cells may be genuine stem cells.40,42,49 These assays transplanted these cells under the renal capsules of immunodeficient ovariectomized mice administered oestradiol and progesterone for eight weeks who were subsequently subjected to nephrectomy. The results showed that all grafts reconstituted tissue similar to the endometrium under the renal capsules.49

Endometrial MSCs in mice

The mouse is a very well-established animal model for studies of endometrial functions. Female mice undergo approximately 80 oestrous cycles throughout their reproductive life. Each cycle lasts four days,26 during which time the endometrium undergoes cellular proliferation and apoptosis cycles. Several studies have been conducted in female mice following the removal of their ovaries (thus removing the main progesterone and oestrogen sources). The following results were obtained: (1) oestrogen-sensitive cells undergo apoptosis; (2) an atrophic endometrium has very few glands; (3) the epithelial lining is dramatically increased; and (4) a dense stroma is generated within a 10- to 14-day period after surgery.50 These studies demonstrated that important regeneration of the endometrium could be induced through the administration of exogenous oestrogen.50-52

The presence of epithelial and endothelial cell populations has also been reported in the endometria of cycling mice expressing mTert (Telomerase reverse transcriptase).53 Because adult stem cells have slow cycles and divide only during tissue replacement to replace lost cells, they can be identified in vivo using the ligase chain reaction (LCR) technique. These studies have been conducted in mouse uteri marked with bromodeoxyuridine (BrdU).52,54-57 BrdU is a molecular analogue of thiamine and is used by the cells in place of the original nitrogen base during cellular multiplication periods. As a result of this procedure, cellular populations with a slow division cycle are identified as stem/progenitor cells or label-retaining cells (LRC),55 whereas cells that divide rapidly (which do not correspond to stem cells) dilute the label. In these studies, immunohistochemistry was also used to locate epithelial, stromal and myometrial cells positive for BrdU, which revealed their locations and some components of the cellular niche.51,54,57 A total of 6 % of stromal cells can be identified as LRCs after a period of 84 days. In these studies, 40 % of the LRCs were located near the endometrium-myometrium union.51

LRCs are negative for CD45 expression.51,57 Additionally, epithelial LRCs lack alpha oestrogen receptor (ER-α) expression, whereas epithelial and stromal neighbour cells (identified as non-label-retaining) are indeed positive for ER-α expression. Hence, oestrogen has been suggested to stimulate endometrial proliferation indirectly through cellular niches for endometrial MSCs.4 However, only a portion of LRCs correspond to stem cells.56

Endometrial MSCs in cows

The presence of cells in the bovine endometrial stroma capable of differentiating in vitro into the osteogenic lineage that possess characteristics related to BM-MSCs has been reported.58 Cabezas et al.59 studied the uteri of healthy Holstein cows at the beginning of the oestrous cycle luteal phase (days 1-5 post-ovulation) and during the luteal phase (between days 13 and 18 post-ovulation) to search for stem cells. These authors were able to identify the expression of markers for embryonic stem cells (OCT4 and SOX2) and MSCs (STAT3, CD44 and c-KIT) in the cow endometria during both periods of the oestrous cycle luteal phase. Cell lines obtained in the late luteal phase were induced to differentiate into the osteogenic and chondrogenic lineages; these differentiations were determined using alizarin crimson and alcian blue staining, respectively.59

Endometrial MSCs in pigs

In pigs, some cells have been isolated from the uterus with the ability to differentiate in vitro into the adipogenic and osteogenic lineages. These cells express MSC markers, such as CD73, CD29, CD90, CD105,32 CD44, CD144, CD105 and CD140b, and are negative for the presence of HSC markers, such as CD34 and CD45.60

Using the Hoechst 33342 fluorescent dye and cytometry analysis, Bodek et al.32 was able to identify side population cells that might be responsible for the regeneration process in the porcine endometrium. Using an antibody against ABCB1 (MDR1), the authors determined that the side population cells resided between the stroma and the epithelial layer in the pig endometrium during the 19th day of the oestrous cycle. In this same work, the stromal cells isolated from the pig endometrium on days 2-4 and 19 of the oestrous cycle proliferated and produced colonies. Moreover, the cells differentiated into the osteogenic, adipogenic and chondrogenic lineages.32

Endometrial MSCs in ewes

The presence of a small population of CD271-positive and CD49-negative stromal cells has been reported in the ewe endometrium. This cell population has a perivascular location, can differentiate into the four mesodermic lineages (adipogenic, osteogenic, chondrogenic and muscular) and shows a high cloning efficiency.61

Immune modulating effects of endometrial MSCs

The uterus is an organ with privileged and unique immunological characteristics that allow it to host a semi-allogeneic organism (foetus) in an exceptionally tolerant environment.62 Many studies have shown that MSCs escape immune recognition and inhibit the immunological response.14,63 MSCs may play an important role in the maintenance of immune homeostasis by preventing the inappropriate activation of T lymphocytes and generating a tolerant environment or stopping the immunological response during reparation.64,65 This function is a very important feature because it facilitates the clinical allogeneic use of these cells in regenerative medicine.

MSCs may inhibit dendritic cell maturation and hence prevent T lymphocyte activation. Additionally, they diminish the proliferation and cytotoxic activity of NK cells.66,67 MSCs have been reported to have low or absent expression of the major histocompatibility complex (MHC) class II protein,14 which represents a great advantage when they are used for allogeneic cell therapy (Figure 1).

 

 

 

figure1

Figure 1. Immunoregulatory ability of MSCs. MSCs regulate the functions of NK cells, dendritic cells (DC) and T lymphocytes. The immunosuppressive effect may occur through the secretion of different factors or through cellular contact (black arrows). The former pathway involves TGFβ, HGF, IL-10, PGE2, and HLA-G5, whereas the latter pathway involves the products of IDO enzyme activity, PD-L1, HLA-G1, ICAM-I and VCAM-I. Pro-inflammatory cytokines (IFN-γ) secreted by NK cells and activated T lymphocytes favour the immunoregulatory activity of MSCs (dotted lines), because they increase or induce the secretion of molecules that regulate the functions of the distinct cellular components of the immune system. Modified from Montesinos et al, and Ma et al.19,66

 

Menstrual endometrial stem cells from healthy women have been shown to inhibit the appropriate differentiation from monocytes into mature dendritic cells in vitro. This effect was attributed to IL-6 and IL-10 production because the levels of these cytokines were increased in the culture medium.68 Due to their immune suppressing properties, MSCs may be a good option for autoimmune diseases, such as systemic lupus erythaematosus, diabetes type I and multiple sclerosis.69 However, the presence of MSCs with immune modulating characteristics must be taken into account in the tumour microenvironment because these cells may have important implications for tumour growth.70 The presence of MSCs in tumours has been suggested to benefit the growth of the tumour via an immune suppressing process that favours the ability of tumour cells to evade the immune system.70 These findings may limit the clinical use of these cells.

Potential clinical applications of endometrial MSCs

Regenerative medicine offers the potential for the replacement or repair of different types of cells within damaged tissues or the tissues themselves, typically through cell therapy or tissue engineering. Stem cells are critical for these approaches; indeed, the involvement of the BM in the differentiation of stem cells to non-haematopoietic cells has been well demonstrated. Furthermore, the contribution of BM-derived stem cells in the promotion of neoangiogenesis has been demonstrated not only in animal models but also in human clinical trials with an excellent safety profile.

Recent evidence indicates that the endometrium is a tissue with the potential for regeneration using these approaches. The presence of donor cells in the endometria of women receiving BM transplantations suggests a haematopoietic source with the ability to renew this tissue. Here, we describe the role of cell therapy with BM-derived stem cells for the treatment of endometrial dysfunction in Asherman’s syndrome and/or endometrial atrophy in humans and murine models. Additionally, the emerging field of tissue engineering has recently been applied to reproductive tissues beyond the endometrium with elegant studies involving humans and animal models.

Currently, most studies on the biology of MSCs have used BM-derived MSCs. Similarly, most of the literature has described the application of MSCs from this source for cell therapy protocols.66,71 Recent evidence indicates that the endometrium can be regenerated by BM-MSCs due to their capacity to promote neoangiogenesis and modify cellular fibrosis. Thus, in a rat model of severe uterine injury, BM-MSCs loaded onto degradable collagen membranes resulted in higher bFGF, IGF-1, TGFβ1 and VEGF levels in the wounded tissue adjacent to the collagen/BM-MSC constructs at four weeks post-transplantation compared to the corresponding tissues in rats who received the collagen construct alone or in the spontaneous regeneration group. Moreover, the collagen/BM-MSC system increased the proliferative abilities of the uterine endometrial and muscular cells, facilitated microvasculature regeneration, and restored the ability of the endometrium to receive an embryo and support its development to a viable stage.72 Moreover, CD133+ BM-derived stem cell (BMDSC) autologous cell therapy may be useful for the treatment of some pathologies, such as patients with refractory Asherman’s syndrome (AS),73-75 which corresponds to a replacement of the endometrial stroma by fibrous tissue and the complete disappearance of the endometrial structure (Donnez and Nisolle, 1994).74,75 Autologous cell therapy using CD133+ BMDSCs in conjunction with hormonal replacement therapy increased the volume and duration of menses as well as the thickness and angiogenic processes of the endometrium while decreasing the intrauterine adhesion scores within the first three months (Santamaría et al., 2016).73,75 Furthermore, BMDSC transplantation in a murine model of Asherman’s syndrome improved fertility in the mice, demonstrating a functional role for these cells in uterine repair.76

Many reproductive alterations are associated with abnormal endometrial proliferation; therefore, endometrial MSCs may perform an important role in the physiopathology of diseases, including human endometriosis, adenomyosis, and infertility problems related to hypoplasia or endometrial atrophy,53 and probably in some important diseases within veterinary medicine, such as cystic endometrial hyperplasia in dogs, equine endometriosis and endometrial cancer. However, these roles have not been demonstrated to date. Endometrial MSCs are responsible for endometrial renovation during each oestrous cycle. Therefore, a decrease in the numbers or functions of these cells may result in a thin endometrium that is unable to support embryonic implantation,77 as occurs in women going through menopause. However, administration of hormone therapy to these women causes the epithelial, stromal and blood vessel cells to proliferate and differentiate.78 Regeneration resulted in the formation of a thick endometrial layer that was able to support gestation even in women over 60 years of age who were able to have children by an in vitro fecundation technique.79 In humans, the possibility of using endometrial MSCs for the treatment of Asherman’s syndrome has been explored. This syndrome is characterized by uterine atrophy and the production of adherences to the endometrium due to trauma, which produces infertility as a consequence.53

In equines, endometriosis is a chronic degenerative disease produced by chronic inflammation that causes infertility in mares; this disease originates in endometrial fibrosis and uterus gland alterations.80-82 Currently, no effective treatments are available for this disease, although the administration of MSCs from adipose tissue has been shown to prevent its progression.83 Therefore, an endometrial MSC treatment for this disease from the same or an allogenic animal source may produce better results. In humans, endometriosis is a chronic disease that is characterized by the presence of endometrial glands and stroma outside of the uterine cavity.84 Endometrial MSCs have been hypothesized to play a significant role in the physiopathology of this disease.53 Currently, efforts are being undertaken to acknowledge the real participation of these cells and to design a strategy for the treatment and control of this disease. Cystic endometrial hyperplasia/pyometra is a poly-systemic disorder that may be chronic or acute, is present in adult female dogs, and is characterized by endometrial hyperplasia associated with high progesterone and oestrogen production that is generally complicated with an ascending infection.85 The pathogenesis of this disorder may be related to the oestrogen-endometrial stem cell interaction. This interaction has been observed in mice, where the presence of endometrial MSCs has been suggested.51 Furthermore, several studies have surgically removed the ovaries to produce endometrial atrophy within a 10- to 14-day period50; then, an important regeneration of these structures was induced by the administration of exogenous oestrogen.50-52 Although there are no reports to date regarding the existence of MSCs in female dogs, this hypothesis is interesting and warrants further study.

Apart from the common mesodermal lineages, endometrial MSCs may be induced to differentiate in vitro into skeletal and cardiac muscle,86,87 insulin-producing cells88 and the urinary epithelium89 in the endodermic lineages and finally into neuronal cells [similar to neurolemmocytes, Schwann cells],90,91 and dopaminergic neurons91 in the ectodermic lineages.28,92,93 Therefore, these cells might be used to treat affections such as cardiac disease, muscle degeneration, diabetes type 1 and neurodegenerative diseases in the future.

The possibility of using endometrial MSCs differentiated into uroepithelial cells along with an adequate scaffolding has been explored to fabricate a transplant substitute for the urinary epithelium for patients with bladder damage due to carcinoma, trauma or infection.89 Recently, the transplant of endometrial MSCs into the caudate nucleus of vervet monkey (Chlorocebus sabaeus) brains induced with Parkinson disease signs through administration of the 1-metil-4 fenil-1, 2, 3,6-tetrahidropiridina (MPTP) neurotoxin has been demonstrated to produce cells with neuronal morphology in vivo that also express tyrosine hydroxylase (TH). Thus, this procedure increases the TH-positive cell numbers to form dopamine metabolite concentrations within the in vivo transplant site. The aforementioned results suggest that endometrial MSCs may be used for the treatment of this disease in the future.94

MSCs may be useful for tumour treatment. In this regard, Han et al.95 reported that the administration of endometrial stem cells either intravenously or intratumourally in a glioma inhibited the growth and reduced the tumour size in more than 45 % of cases; these effects were associated with the inhibition of neo-vascularization.95

The endometrium is the site where physiological angiogenesis occurs in adults. This process uses regenerative cells that cyclically form tissues, which detach without leaving any scars.96 Angiogenesis is crucial in the context of cardiac regeneration (after one year) due to ischaemic damage.96 The uterus has been demonstrated to be a source or progenitor cells that induce angiogenesis when injected into a heart that has suffered infarction.97

Some immune privileged sites in organisms have low or absent MHC I protein expression on their cell surfaces.98 The uterus has a high percentage (> 20 %) of cells that are MHC I-negative 96; however, whether these cells are stem cells has not been proven. The benefits of an intramyocardial injection of MHC I-negative allogeneic cells after a myocardial infarct are comparable to those of syngeneic BM cell transplants. MHC I-negative cells have been reported to preserve cardiac functions, decrease the infarct size and improve regeneration after a myocardial infarction.96

Human endometrial MSCs may restore functions in damaged ovaries. Mice subjected to ovary damaged through busulfan and cyclophosphamide administration (both drugs produce toxicity to germinal cells) followed by experimental treatment with an intravenous injection of endometrial MSCs exhibited improvements in weight and oestrous cycle presentation and restored fertility. Exhaustion of the germinal stem cell reserve induced by chemotherapy was also decreased.99 This evidence suggests a possible use of these cells as a cellular therapy for patients undergoing chemotherapy.

In addition to the reproductive scope, endometrial MSCs could be used in other fields of veterinary medicine for the treatment of a large number of diseases, such as (a) autoimmune diseases (i.e., rheumatoid arthritis, systemic erythaematosus lupus, and diabetes type 1), (b) cardiac affections (i.e., cardiac insufficiency), (c) lesions of the musculoskeletal apparatus (i.e., muscle degeneration, articular cartilage alterations, which are particularly important in equine osteoarthritis, and hip dysplasia in dogs), (d) urinary tract diseases (i.e., renal insufficiency), (e) neurodegenerative processes and spinal cord injuries, (f) tumour treatment by inhibiting the growth and reducing the tumour size, (g) development of pharmacological products for the study of drug toxicity or in vitro efficacy, and finally (h) the generation of animal models for the study of human diseases and diseases of veterinary interest. Additionally, endometrial MSCs may become an important tool for veterinary tissue engineering and regenerative veterinary medicine.100-102

Conclusions

The immune modulating capacity of MSCs facilitates their allogeneic clinical use in regenerative medicine and may have important implications for tumour growth. The endometrium is an alternative and accessible source of MSCs in humans, mice, cows, pigs and ewes. However, this capacity must be determined in these cells. In addition to the common mesodermic lineages, endometrial MSCs can differentiate into the endodermic and ectodermic lineages. Thus, in the future, these cells might be used to treat affections, such as cardiac disease, muscle degeneration, diabetes type 1 and neurodegenerative diseases.

The study of endometrial MSCs in domestic animals is a new and promising field because our improved understanding of the physiology and biology of these cells will help elucidate the physiopathology of reproductive diseases, such as cystic endometrial hyperplasia in dogs and equine endometriosis, and contribute to the proposal of new treatments. MSC studies can also help clarify and treat infertility problems due to hypoplasia or endometrial atrophy.

Although the endometrium seems to be a promising source of MSCs, several assays must be conducted before possible clinical applications can be considered. Furthermore, many basic investigations need to be performed to compare the biological aspects of these cells with other MSC sources, especially the bone marrow.

Funding

This work was supported in part by Project PAPIIT IN216412 Dirección General de Asuntos del Personal Académico (DGAPA) de la UNAM.

Research in the Dr Montesinos’ laboratory is supported by grants from the Mexican Institute of Social Security (IMSS, grant no. 1311) and the National Council of Science and Technology (CONACYT, grant no. 258205), Mexico.

Acknowledgements

The authors would like to thank Diana Escalante Meléndez for the translation of the manuscript into the English language

Conflicts of interest

The authors declare that they do not have any conflict of interest.

Author contributions

Ana Gabriela Serrato López: Writing and review of the manuscript, analytical review of the final version. (This review forms part of his undergraduate thesis with which he obtained the title).
Juan José Montesinos Montesinos: Writing and analytical review of the manuscript (he is an expert investigator in the area of mesenchymal stem cells).
Santiago René Anzaldúa Arce: Conception and adaptation of the central themes of the article, writing, analytical review, correction and conformation of the final version, is also the author responsible.

References

1. Gargett CE, Schwab KE, Zillwood RM, Nguyen HPT, Wu D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod. 2009;80:1136-45. doi: 10.1095/biolreprod.108.075226.

2. McLennan CE, Rydell AH. Extent of endometrial shedding during normal menstruation. Obstet Gynecol. 1965;26:605-21.

3. Slayden OD, Brenner RM. Hormonal regulation and localization of estrogen, progestin and androgen receptors in the endometrium of nonhuman primates: effects of progesterone receptor antagonists. Arch Histol Cytol. 2004;67:393-409.

4. Gargett CE. Uterine stem cells: What is the evidence? Hum Reprod Update. 2007;13:87-101. doi: 10.1093/humupd/dml045.

5. Prianishnikov VA. On the concept of stem cell and a model of functional-morphological structure of the endometrium. Contraception. 1978;18:213-23.

6. Hartman CG. Regeneration of the monkey uterus after surgical removal of the endometrium and accidental endometriosis. West J Surg. 1944;52:87-102.

7. Tresserra F, Grases P, Ubeda A, Pascual MA, Grases PJ, Labastida R. Morphological changes in hysterectomies after endometrial ablation. Hum Reprod. 1999;14:1473-77.

8. Abbott JA, Garry R. The surgical management of menorrhagia. Hum Reprod Update. 2002;8:68-78.

9. Wood C, Rogers P. A pregnancy after planned partial endometrial resection. Aust N Z J Obstet Gynaecol. 1993;33:316-8. doi: 10.1111/j.1479-828X.1993.tb02097.x.

10. Bird CC, Willis RA. The production of smooth muscle by the endometrial stroma of the adult human uterus. J Pathol Bacteriol. 1965;90:75-81.

11. Mazur MT, Kraus FT. Histogenesis of morphologic variations in tumors of the uterine wall. Am J Surg Pathol. 1980;4:59-74.

12. Roth E, Taylor HB. Heterotopic cartilage in the uterus. Obstet Gynecol. 1966;27:838-44.

13. Chan RWS. Clonogenicity of Human Endometrial Epithelial and Stromal Cells. Biol Reprod. 2004;70:1738-50. doi: 10.1095/biolreprod.103.024109.

14. Gazit Z, Pelled G, Sheyn D, Kimelman N, Gazit D. Mesenchymal Stem Cells. In: Lanza R, Atala A, editors. Essentials of Stem Cell Biology. 3rd ed. San Diego, CA (US): Academic Press; 2013. p. 255-66.

15. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143-7. doi: 10.1126/science.284.5411.143.

16. Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–95.

17. Verdi J, Tan A, Shoae-Hassani A, Seifalian AM. Endometrial stem cells in regenerative medicine. J Biol Eng. 2014;8:20.

18. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315-7. doi: 10.1080/14653240600855905.

19. Montesinos JJ, Castro-Manrreza E. Células troncales mesenquimales. In: Pelayo R, Santa-Olalla J, Velasco I, editors. Células troncales y medicina regenerativa. Ciudad de México (MX): Universidad Nacional Autónoma de México; 2011. p. 119-41.

20. Ulrich D, Muralitharan R, Gargett CE. Toward the use of endometrial and menstrual blood mesenchymal stem cells for cell-based therapies. Expert Opin Biol Ther. 2013;13:1387-400. doi: 10.1517/14712598.2013.826187.

21. Kobayashi A, Behringer RR. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet. 2003;4:969-80. doi: 10.1038/nrg1225.

22. Snyder EY, Loring JF. A role for stem cell biology in the physiological and pathological aspects of aging: Role for stem cell biology in aging. J Am Geriatr Soc. 2005;53:S287-S91. doi: 10.1111/j.1532-5415.2005.53491.x.

23. Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function? Cell. 2001;105:829–41.

24. Körbling M, Estrov Z. Adult stem cells for tissue repair—a new therapeutic concept? New England Journal of Medicine. 2003;349:570–82.

25. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292:81–5.

26. Cervelló I, Gil-Sanchis C, Mas A, Faus A, Sanz J, Moscardó F, et al. Bone marrow-derived cells from male donors do not contribute to the endometrial side population of the recipient. PLoS ONE. 2012;7:e30260. doi: 10.1371/journal.pone.0030260.

27. Gargett CE, Nguyen HPT, Ye L. Endometrial regeneration and endometrial stem/progenitor cells. Rev Endocr Metab Disord. 2012;13:235-51. doi: 10.1007/s11154-012-9221-9.

28. Shirian S, Ebrahimi-Barough S, Saberi H, Norouzi-Javidan A, Mousavi SMM, Derakhshan MA, et al. Comparison of capability of human bone marrow mesenchymal stem cells and endometrial stem cells to differentiate into motor neurons on electrospun poly(ε-caprolactone) scaffold. Mol Neurobiol. 2016;53:5278-87. doi: 10.1007/s12035-015-9442-5.

29. Dimitrov R, Timeva T, Kyurkchiev D, Stamenova M, Shterev A, Kostova P, et al. Characterization of clonogenic stromal cells isolated from human endometrium. Reproduction. 2008;135:551-8. doi: 10.1530/REP-07-0428.

30. Cho NH, Park YK, Kim YT, Yang H, Kim SK. Lifetime expression of stem cell markers in the uterine endometrium. Fertil Steril. 2004;81:403-7. doi: 10.1016/j.fertnstert.2003.07.015.

31. Matthai C. Oct-4 expression in human endometrium. Mol Hum Reprod. 2006;12:7-10. doi: 10.1093/molehr/gah254.

32. Bodek G, Bukowska J, Wisniewska J, Ziecik AJ. Evidence for the presence of stem/progenitor cells in porcine endometrium: stem/progenitor cells in porcine endometrium. Mol Reprod Dev. 2015;82:182-90. doi: 10.1002/mrd.22459.

33. Lynch L, Golden-Mason L, Eogan M, O’Herlihy C, O’Farrelly C. Cells with haematopoietic stem cell phenotype in adult human endometrium: relevance to infertility? Hum Reprod. 2007;22:919-26. doi: 10.1093/humrep/del456.

34. Meng X, Ichim TE, Zhong J, Rogers A, Yin Z, Jackson J, et al. Endometrial regenerative cells: a novel stem cell population. J Transl Med. 2007;5:57. doi: 10.1186/1479-5876-5-57.

35. Schwab KE, Gargett CE. Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Hum Reprod. 2007;22:2903-11. doi: 10.1093/humrep/dem265.

36. Masuda H, Anwar SS, Bühring H-J, Rao JR, Gargett CE. A Novel Marker of Human Endometrial Mesenchymal Stem-Like Cells. Cell Transplant. 2012;21:2201-14. doi: 10.3727/096368911X637362.

37. Ishikawa M, Nakayama K, Yeasmin S, Katagiri A, Iida K, Nakayama N, et al. NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma. Int J Oncol. 2010;36:1097-103.

38. Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, et al. A protein interaction network for pluripotency of embryonic stem cells. Nature. 2006;444:364-8. doi: 10.1038/nature05284.

39. Gargett CE, Zillwood RM, Schwab KE, Naqvi SZ. 236. Characterising the stem cell activity of human endometrial epithelial and stromal cells. Reprod Fertil Dev. 2005;17(9):93-. doi: 10.1071/SRB05Abs236.

40. Cervelló I, Gil-Sanchis C, Mas A, Delgado-Rosas F, Martínez-Conejero JA, Galán A, et al. Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. PLoS ONE. 2010;5:e10964. doi: 10.1371/journal.pone.0010964.

41. Bockeria L, Bogin V, Bockeria O, Le T, Alekyan B, Woods EJ, et al. Endometrial regenerative cells for treatment of heart failure: a new stem cell enters the clinic. J Transl Med. 2013;11(1):56. doi: 10.1186/1479-5876-11-56.

42. Cervelló I, Mas A, Gil-Sanchis C, Peris L, Faus A, Saunders PTK, et al. Reconstruction of endometrium from human endometrial side population cell lines. PLoS ONE. 2011;6:e21221. doi: 10.1371/journal.pone.0021221.

43. Wada-Hiraike O, Hiraike H, Okinaga H, Imamov O, Barros RPA, Morani A, et al. Role of estrogen receptor β in uterine stroma and epithelium: Insights from estrogen receptor β−/− mice. PNAS. 2006;103(4):18350–5. doi: 10.1073/pnas.0608861103.

44. Masuda H, Maruyama T, Hiratsu E, Yamane J, Iwanami A, Nagashima T, et al. Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/γcnull immunodeficient mice. PNAS. 2007;104:1925–30.

45. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996;183:1797-806.

46. Bunting KD, Zhou S, Lu T, Sorrentino BP. Enforced P-glycoprotein pump function in murine bone marrow cells results in expansion of side population stem cells in vitro and repopulating cells in vivo. Blood. 2000;96:902–9.

47. Scharenberg CW, Harkey MA, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood. 2002;99:507–12.

48. Smalley MJ, Clarke RB. The mammary gland “side population”: a putative stem/progenitor cell marker? J Mammary Gland Biol Neoplasia. 2005;10:37-47. doi: 10.1007/s10911-005-2539-0.

49. Miyazaki K, Maruyama T, Masuda H, Yamasaki A, Uchida S, Oda H, et al. Stem cell-like differentiation potentials of endometrial side population cells as revealed by a newly developed in vivo endometrial stem cell assay. PLoS ONE. 2012;7:e50749. doi: 10.1371/journal.pone.0050749.

50. Chan RWS, Kaitu’u-Lino Tu, Gargett CE. Role of label-retaining cells in estrogen-induced endometrial regeneration. Reprod Sci. 2012;19:102-14. doi: 10.1177/1933719111414207.

51. Chan RWS, Gargett CE. Identification of label-retaining cells in mouse endometrium. Stem Cells. 2006;24:1529-38. doi: 10.1634/stemcells.2005-0411.

52. Martin L, Finn CA. Interactions of oestradiol and progestins in the mouse uterus. J Endocrinol. 1970;48:109–15.

53. Deane JA, Ong YR, Cain JE, Jayasekara WSN, Tiwari A, Carlone DL, et al. The mouse endometrium contains epithelial, endothelial and leucocyte populations expressing the stem cell marker telomerase reverse transcriptase. Mol Hum Reprod. 2016;22:272-84. doi: 10.1093/molehr/gav076.

54. Cervelló I, Martínez-Conejero JA, Horcajadas JA, Pellicer A, Simón C. Identification, characterization and co-localization of label-retaining cell population in mouse endometrium with typical undifferentiated markers. Hum Reprod. 2007;22:45-51. doi: 10.1093/humrep/del332.

55. Braun KM, Watt FM. Epidermal label-retaining cells: background and recent applications. J Investig Dermatol Symp Proc. 2004;9(3):196–201. doi: 10.1111/j.1087-0024.2004.09313.x.

56. Li Y, Rosen JM. Stem/progenitor cells in mouse mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2005;10:17-24. doi: 10.1007/s10911-005-2537-2.

57. Szotek PP, Chang HL, Zhang L, Preffer F, Dombkowski D, Donahoe PK, et al. Adult mouse myometrial label-retaining cells divide in response to gonadotropin stimulation. Stem Cells. 2007;25:1317-25. doi: 10.1634/stemcells.2006-0204.

58. Donofrio G, Franceschi V, Capocefalo A, Cavirani S, Sheldon I. Bovine endometrial stromal cells display osteogenic properties. Reproductive Biology and Endocrinology. 2008;6:65. doi: 10.1186/1477-7827-6-65.

59. Cabezas J, Lara E, Pacha P, Rojas D, Veraguas D, Saravia F, et al. The endometrium of cycling cows contains populations of putative mesenchymal progenitor cells. Reprod Domest Anim. 2014;49:550-9. doi: 10.1111/rda.12309.

60. Miernik K, Karasinski J. Porcine uterus contains a population of mesenchymal stem cells. Reproduction. 2012;143:203-9. doi: 10.1530/REP-11-0202.

61. Letouzey V, Tan KS, Deane JA, Ulrich D, Gurung S, Ong YR, et al. Isolation and characterisation of mesenchymal stem/stromal cells in the ovine endometrium. PLos ONE. 2015;10:e0127531. doi: 10.1371/journal.pone.0127531.

62. Arck P, Solano ME, Walecki M, Meinhardt A. The immune privilege of testis and gravid uterus: Same difference? Mol Cell Endocrinol. 2014;382:509-20. doi: 10.1016/j.mce.2013.09.022.

63. Popp FC, Renner P, Eggenhofer E, Slowik P, Geissler EK, Piso P, et al. Mesenchymal stem cells as immunomodulators after liver transplantation. Liver Transpl. 2009;15:1192-8. doi: 10.1002/lt.21862.

64. Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Immunobiology of mesenchymal stem cells. Cell Death Differ. 2014;21:216. doi: 10.1038/cdd.2013.158.

65. Prockop DJ, Youn Oh J. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther. 2012;20:14-20. doi: 10.1038/mt.2011.211.

66. Castro-Manrreza ME, Montesinos JJ. Immunoregulation by mesenchymal stem cells: Biological aspects and clinical applications. J Immunol Res. 2015;2015:1-20. doi: 10.1155/2015/394917.

67. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells. 2006;24:74-85. doi: 10.1634/stemcells.2004-0359.

68. Bozorgmehr M, Moazzeni SM, Salehnia M, Sheikhian A, Nikoo S, Zarnani A-H. Menstrual blood-derived stromal stem cells inhibit optimal generation and maturation of human monocyte-derived dendritic cells. Immunol Lett. 2014;162:239-46. doi: 10.1016/j.imlet.2014.10.005.

69. Ghannam S, Bouffi C, Djouad F, Jorgensen C, Noël D. Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res Ther. 2010;1:2. doi: 10.1186/scrt2.

70. Montesinos JJ, Mora-García MdL, Mayani H, Flores-Figueroa E, García-Rocha R, Fajardo-Orduña GR, et al. In vitro evidence of the presence of mesenchymal stromal cells in cervical cancer and their role in protecting cancer cells from cytotoxic T cell activity. Stem Cells Dev. 2013;22:2508-19. doi: 10.1089/scd.2013.0084.

71. Fajardo-Orduña GR, Mayani H, Castro-Manrreza ME, Flores-Figueroa E, Flores-Guzmán P, Arriaga-Pizano L, et al. Bone marrow mesenchymal stromal cells from clinical scale culture: in vitro evaluation of their differentiation, hematopoietic support, and immunosuppressive capacities Stem Cells Dev. 2016;25(17):1299-310. doi: 10.1089/scd.2016.0071.

72. Ding L, Li Xa, Sun H, Su J, Lin N, Péault B, et al. Transplantation of bone marrow mesenchymal stem cells on collagen scaffolds for the functional regeneration of injured rat uterus. Biomaterials. 2014;35:4888-900. doi: 10.1016/j.biomaterials.2014.02.046.

73. Cervelló I, Santamaría X, Miyazaki K, Maruyama T, Simón C. Cell therapy and tissue engineering from and toward the uterus. Semin Reprod Med. 2015;33:366-72. doi: 10.1055/s-0035-1559581.

74. Donnez J, Nisolle M. An Atlas of Laser Operative Laparoscopy and Hysteroscopy (Encyclopedia of Visual Medicine Series). Chicago, IL (US): Parthenon Pub; 1994.

75. Santamaria X, Cabanillas S, Cervelló I, Arbona C, Raga F, Ferro J, et al. Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman’s syndrome and endometrial atrophy: a pilot cohort study. Hum Reprod. 2016;31:1087-96. doi: 10.1093/humrep/dew042.

76. Alawadhi F, Du H, Cakmak H, Taylor HS. Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman’s syndrome. PLoS ONE. 2014;9. doi: 10.1371/journal.pone.0096662.

77. Gargett CE, Healy DL. Generating receptive endometrium in Asherman’s syndrome. J Hum Reprod Sci. 2011;4(1):49-52.

78. Ettinger B, Bainton L, Upmails DH, Citron JT, VanGessel A. Comparison of endometrial growth produced by unopposed conjugated estrogens or by micronized estradiol in postmenopausal women. Am J Obstet Gynecol. 1997;176:112-7.

79. Paulson RJ, Boostanfar R, Saadat P, Mor E, Tourgeman DE, Slater CC, et al. Pregnancy in the sixth decade of life: obstetric outcomes in women of advanced reproductive age. JAMA. 2002;288:2320-3. doi: 10.1001/jama.288.18.2320.

80. Aresu L, Benali S, Giannuzzi D, Mantovani R, Castagnaro M, Falomo ME. The role of inflammation and matrix metalloproteinases in equine endometriosis. J Vet Sci. 2012;13:171-7. doi: 10.4142/jvs.2012.13.2.171.

81. Hoffmann C, Ellenberger C, Mattos RC, Aupperle H, Dhein S, Stief B, et al. The equine endometrosis: new insights into the pathogenesis. Anim Reprod Sci. 2009;111:261-78. doi: 10.1016/j.anireprosci.2008.03.019.

82. Kenney RM. The etiology, diagnosis and classification of chronic degenerative endometritis. Equine Vet J. 1992;25:186.

83. Mambelli LI, Mattos RC, Winter GHZ, Madeiro DS, Morais BP, Malschitzky E, et al. Changes in expression pattern of selected endometrial proteins following mesenchymal stem cells infusion in mares with endometrosis. PLoS ONE. 2014;9:e97889. doi: 10.1371/journal.pone.0097889.

84. Seli E, Berkkanoglu M, Arici A. Pathogenesis of endometriosis. Obstet Gynecol Clin North Am. 2003;30:41-61.

85. Arora N, Sandford J, Browning GF, Sandy JR, Wright PJ. A model for cystic endometrial hyperplasia/pyometra complex in the bitch. Theriogenology. 2006;66:1530-6. doi: 10.1016/j.theriogenology.2006.02.019.

86. Cui C-H, Uyama T, Miyado K, Terai M, Kyo S, Kiyono T, et al. Menstrual blood-derived cells confer human dystrophin expression in the murine model of duchenne muscular dystrophy via cell fusion and myogenic transdifferentiation. Mol Biol Cell. 2007;18(5):1586-94. doi: 10.1091/mbc.E06-09-0872.

87. Hida N, Nishiyama N, Miyoshi S, Kira S, Segawa K, Uyama T, et al. Novel cardiac precursor-like cells from human menstrual blood-derived mesenchymal cells. Stem Cells. 2008;26(7):1695-704. doi: 10.1634/stemcells.2007-0826.

88. Santamaria X, Massasa EE, Feng Y, Wolff E, Taylor HS. Derivation of insulin producing cells from human endometrial stromal stem cells and use in the treatment of murine diabetes. Mol Ther. 2011;19:2065-71. doi: 10.1038/mt.2011.173.

89. Shoae-Hassani A, Mortazavi-Tabatabaei SA, Sharif S, Seifalian AM, Azimi A, Samadikuchaksaraei A, et al. Differentiation of human endometrial stem cells into urothelial cells on a three-dimensional nanofibrous silk-collagen scaffold: an autologous cell resource for reconstruction of the urinary bladder wall: human endometrial stem cell differentiation into urothelial cells. J Tissue Eng Regen Med. 2015;9:1268-76. doi: 10.1002/term.1632.

90. Bayat N, Ebrahimi-Barough S, Ardakan MMM, Ai A, Kamyab A, Babaloo N, et al. Differentiation of human endometrial stem cells into Schwann cells in fibrin hydrogel as 3D culture. Mol Neurobiol. 2016;53:7170-6. doi: 10.1007/s12035-015-9574-7.

91. Wolff EF, Gao XB, Yao KV, Andrews ZB, Du H, Elsworth JD, et al. Endometrial stem cell transplantation restores dopamine production in a Parkinson’s disease model. J Cell Mol Med. 2011;15(4):747-55. doi: 10.1111/j.1582-4934.2010.01068.x.

92. Fayazi M, Salehnia M, Ziaei S. Differentiation of human CD146-positive endometrial stem cells to adipogenic-, osteogenic-, neural progenitor-, and glial-like cells. In Vitro Cell Dev Biol Anim. 2015;51:408-14. doi: 10.1007/s11626-014-9842-2.

93. Patel AN, Park E, Kuzman M, Benetti F, Silva FJ, Allickson JG. Multipotent menstrual blood stromal stem cells: isolation, characterization, and differentiation. Cell Transplant. 2008;17:303–11.

94. Wolff EF, Mutlu L, Massasa EE, Elsworth JD, Redmond Jr DE, Taylor HS. Endometrial stem cell transplantation in MPTP- exposed primates: an alternative cell source for treatment of Parkinson’s disease. J Cell Mol Med. 2014;19:249-56. doi: 10.1111/jcmm.12433.

95. Han X, Meng X, Yin Z, Rogers A, Zhong J, Rillema P, et al. Inhibition of intracranial glioma growth by endometrial regenerative cells. Cell Cycle. 2009;8:606-10. doi: 10.4161/cc.8.4.7731.

96. Ludke A, Wu J, Nazari M, Hatta K, Shao Z, Li S-H, et al. Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy. J Mol Cell Cardiol. 2015;84:116-28. doi: 10.1016/j.yjmcc.2015.04.019.

97. Huang ML, Tian H, Wu J, Matsubayashi K, Weisel RD, Li RK. Myometrial cells induce angiogenesis and salvage damaged myocardium. Am J Physiol Heart Circ Physiol. 2006;291:H2057-H66. doi: 10.1152/ajpheart.00494.2006.

98. Ito T, Meyer KC, Ito N, Paus R. Immune privilege and the skin. Curr Dir Autoimmun. 2008;10:27-52. doi: 10.1159/000131412.

99. Lai D, Wang F, Yao X, Zhang Q, Wu X, Xiang C. Human endometrial mesenchymal stem cells restore ovarian function through improving the renewal of germline stem cells in a mouse model of premature ovarian failure. J Transl Med. 2015;13:155. doi: 10.1186/s12967-015-0516-y.

100. Baiguera S, Jungebluth P, Mazzanti B, Macchiarini P. Mesenchymal stromal cells for tissue-engineered tissue and organ replacements: Tissue engineering and stem cells. Transpl Int. 2012;25:369-82. doi: 10.1111/j.1432-2277.2011.01426.x.

101. Gattegno-Ho D, Argyle S-A, Argyle DJ. Stem cells and veterinary medicine: tools to understand diseases and enable tissue regeneration and drug discovery. Vet J. 2012;191:19-27. doi: 10.1016/j.tvjl.2011.08.007.

102. Gonçalves N, Ambrósio C, Piedrahita J. Stem cells and regenerative medicine in domestic and companion animals: a multispecies perspective. Reprod Domest Anim. 2014;49:2-10. doi: 10.1111/rda.12392.

 

Refbacks

  • There are currently no refbacks.