Monthly changes in the endometrial cycle indicate the presence of endometrial stem cells. In recent years, various stem cells that exist in the endometrium have been identified and characterized. Additionally, many studies have shown that Bone Marrow Mesenchymal Stem Cells (BM-MSCs) provide an alternative source for regenerating the endometrium and repairing endometrial injury. This review discusses the origin of endometrial stem cells, the characteristics and main biomarkers among five types of putative endometrial stem cells, applications of endometrium-derived stem cells and menstrual blood-derived stem cells, the association between BM-MSCs and endometrial stem cells, and progress in repairing endometrial injury.

Abstract. The objective of the present study was to examine whether Clostridium butyricum supplementation has a role in the regulation of the intestinal flora and the development of the immune system of neonatal mice. A total of 30 pregnant BALB/c mice, including their offspring, were randomly divided into three groups: In the maternal intervention group (Ba), maternal mice were treated with Clostridium butyricum from birth until weaning at postnatal day 21 (PD21) followed by administration of saline to the offspring at PD21-28; in the offspring intervention group (Ab), breast-feeding maternal mice were supplemented with saline and offspring were directly supplemented with Clostridium butyricum from PD21-28; in the both maternal and offspring intervention group (Bb), both maternal mice and offspring were supplemented with Clostridium butyricum at PD 0-21 and at PD21-28. While mice in the control group were given the same volume of normal saline. Stool samples from the offspring were collected at PD14, -21 and -28 to observe the intestinal flora by colony counts of Enterococcus spp., Enterobacter spp., Bifidobacterium spp. and Lactobacillus spp. Detection of intestinal secreted immunoglobulin A (sIgA) levels and serum cytokine (interferon-γ, and interleukin-12, -4 and -10) levels in offspring was performed to evaluate the effect on their immune system. The results revealed that compared with the control group, offspring in the Ba group displayed significantly decreased stool colony counts of Enterococcus spp. (t=3.123, P<0.01) at PD14 and significantly decreased counts of Enterobacter spp. at P<0.05 and t=2.292, P<0.05, respectively). Compared with the control group, the stool colony counts of Bifidobacterium spp. and Lactobacillus spp. were significantly increased in the Ba group at PD21 (t=3.085, P<0.01 and t=2.8508, P<0.05, respectively). The Ab group had significantly higher stool colony counts of Bifidobacterium spp. and Lactobacillus spp. at PD28, compared with the control group (Q=7.679, P<0.01 and Q=6.149, P<0.01, respectively). There were no significant differences identified in the sIgA levels of the intestinal fluid and serum cytokine levels between the control group and the intervention groups. In conclusion, Clostridium butyricum administered to breast-feeding maternal mice was able to regulate the intestinal flora balance in their offspring. However, due to insignificant effects on sIgA level and the associated cytokines, Clostridium butyricum had a limited influence on the balance of type 1 vs. type 2 T-helper cells. However, using Clostridium butyricum as an invention may be a safe method for improving the balance of intestinal flora and associated processes in offspring.

STUDY QUESTION What are the localization, characteristics and potential for tissue regeneration of two perivascular stem cells, namely CD34+ adventitial cells and CD146+ pericytes, in human endometrium? SUMMARY ANSWER Human endometrial CD34+ adventitial cells (located in the outermost layer of blood vessels and mainly in the basal layer) and CD146+ pericytes showed mesenchymal stem cell (MSC) phenotypes in in vitro culture, but presented limited potential to regenerate endometrium. WHAT IS KNOWN ALREADY Periodic endometrial regeneration is considered to be maintained by MSCs. Blood vessel wall, regarded as stem cell niche, harbors a large reserve of progenitor cells that may be integral to the origin of MSCs. However, a lack of validated markers has hampered the isolation of putative endometrial MSCs. Currently, CD146+ pericytes and Sushi Domain Containing 2 (SUSD2) positive cells have been identified in the endometrial perivascular region as sharing MSCs characteristics. STUDY DESIGN, SIZE, DURATION The locations of adventitial cells and pericytes in the human endometrium were identified by immunofluorescence staining (n = 4). After CD34+CD146−CD45−CD56−CD144− adventitial cells and CD146+CD34−CD45−CD56−CD144− pericytes were isolated from the endometrium of normal women (n = 6) by fluorescence-activated cell sorting, their characteristics were investigated in culture. Adventitial cells and pericytes were induced to differentiate, respectively, into vascular endothelial-like cells or endometrial stromal-like cells in vitro, with their potential explored by in vivo xenotransplantation (n = 2 in each group) and eutopic transplantation (n = 2 in each group). PARTICIPANTS/MATERIALS, SETTING, METHODS CD34+ adventitial cells and CD146+ pericytes were cultured in the inducing medium to differentiate into endothelial-like cells in vitro, and then analyzed for CD31, von Willebrand factor immunofluorescent staining and tube formation. They were also cultured to differentiate into endometrial stromal cells in vitro, with the expression of vimentin and CD13 being detected by western blot before and after induction, and the expression of prolactin and insulin-like growth factor-binding protein 1 being determined as well. Single dispersed CD34+ adventitial cells and CD146+ pericytes were respectively transplanted under the kidney capsule of NOG mice to investigate their differentiation potential in vivo. A eutopic transplantation model was constructed by grafting recellularized uterine matrix loaded up with CM-Dil labeled adventitial cells or pericytes into the injury region of nude rat’s uterus. MAIN RESULTS AND THE ROLE OF CHANCE CD34+ adventitial cells were mainly located at the outmost layer of endometrial large vessels, while CD146+ pericytes were found surrounding the inner endothelial cells of microvessels. A small proportion of CD34+ adventitial cells expressed SUSD2. The number of adventitial cells was ∼40 times higher than that of pericytes in the endometrium. Both adventitial cells and pericytes showed MSC phenotypes after in vitro culture. After in vitro induction into endometrial endothelial-like cells and stromal-like cells, adventitial cells showed higher plasticity than pericytes and a closer correlation with stromal-like cells. In the mouse xenotransplantation model, vimentin+ cells, CD31+ endothelial-like cells and CD146+ pericyte-like cells could be observed after adventitial cells were transplanted. CM-Dil-labeled adventitial cells or pericytes could survive in the immunocompromised nude rats after eutopic transplantation, and vimentin+ cells were detected. In addition, CM-Dil-labeled adventitial cells or pericytes did not express α-smooth muscle actin or E-cadherin after transplantation LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION CD34 was chosen as a novel marker to isolate adventitial cells from human endometrium according to previous literature. The association of endometrial CD34+ adventitial cells and SUSD2+ MSCs should be further investigated. WIDER IMPLICATIONS OF THE FINDINGS The decellularized uterine matrix model might be useful in endometrial stem cell therapy. STUDY FUNDING/COMPETING INTEREST(S) L.D. is supported by grants from National Key Research and Development Program of China (2018YFC1004700), Nature Science Foundation of China (81871128, 81571391) and Nanjing Medical Science Development Project (ZKX16042). H.S. is supported by a grant from Jiangsu Province Social Development Project (BE2018602). X.Z. was supported by grants from the Postgraduate Innovative Project of Jiangsu Province (KYCX19-1177). The authors declare no conflict of interest.

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