Current Status of Stem Cells in the Treatment of Premature Ovarian Failure

Premature ovarian failure (POF) is a prevalent cause of female infertility. POF features include estrogen hypofunction, amenorrhea, infertility, and high gonadotropin levels. The etiology of POF is genetic diseases, autoimmune diseases, enzyme defects and environmental factors. The development of Regenerative medicine has made stem cell and exosome (EXOs) therapy effective for POF. This review discusses POF stem cell research and development.

Application of mesenchymal stem cell therapy for premature ovarian insufficiency: Recent advances from mechanisms to therapeutics

The incidence of premature ovarian insufficiency(POI)is increasing worldwide,particularly among younger women,posing a significant challenge to fertility.In addition to menopausal symptoms,POI leads to several complications that profoundly affect female reproductive function and overall health.Unfortunately,current clinical treatment strategies for this condition are limited and often yield unsatisfactory outcomes.These approaches typically involve hormone repla-cement therapy combined with psychological support.Recently,mesenchymal stem cell(MSC)therapies for POI have garnered considerable attention in global research.MSCs can restore ovarian reproductive and endocrine functions through diverse mechanisms,including controlling differentiation,promoting angiogenesis,regulating ovarian fibrosis,inhibiting apoptosis,enhancing autocrine and paracrine effects,suppressing inflammation,modulating the immune system,and genetic regulation.This editorial offers a succinct summary of the application of MSC therapy in the context of POI,providing evidence for groundbreaking medical approaches that have potential to enhance reproductive health and overall well-being for women.

Ovarian function in patients with systemic lupus erythematosus:Pathogenesis,drug application and prospective therapies

Systemic lupus erythematosus(SLE)is a chronic autoimmune disease in which multiple organs are damaged that prevails in fertile women.Currently,glucocorticoids and immunosuppressants are widely used to treat SLE patients.However,ovarian dysfunction occurs following the use of these drugs in women with SLE.Here,we summarize recent progress in terms of understanding ovarian injury,the effects of drug application and strategies to improve ovarian function in women with SLE.This review could be helpful to precisely cure SLE in women desiring to have offspring.

Ability of human umbilical cord mesenchymal stem cells to repair chemotherapy-induced premature ovarian failure

BACKGROUND Premature ovarian insufficiency(POI)and premature ovarian failure(POF)have become one of the major problems threatening women of childbearing age.Studies have shown that stem cells transplanted from bone marrow,umbilical cord,peripheral blood and amniotic fluid can migrate and proliferate to the ovary,promote ovarian function repair,increase the number of follicles and granulosa cells at all levels of ovary,improve endocrine function,and can differentiate into oocytes in specific ovarian environment to restore fertility to some extent.AIM To study the ability of human umbilical cord mesenchymal stem cells(hUCMSCs)to repair ovarian injury after chemotherapy.METHODS A total of 110 female BALB/c mice(aged 7-8 wk old)with body masses of 16.0-20.0 g were selected.The mice were fed until 12 wk of age,and cyclophosphamide was administered by intraperitoneal injection for 14 consecutive days to induce premature ovarian failure in mice.Seventy-five mice with estrous cycle disorder were screened and randomly divided into 3 groups according to their body weight:model group,positive control group and hUCMSC group,and each group had 25 mice.Another 25 mice were used as negative controls.The mice in the hUCMSC group were injected with hUCMSCs in the tail vein,and the mice in the positive control group were given an oestradiol valerate solution and a medroxyprogesterone acetate solution in the tail vein.On the 1^st,15^th,30^th,45^th,and 60^th days after intravenous administration,vaginal smears were made to monitor the estrous cycles of the mice.The ovaries were weighed,and pathological sections were made to observe the morphology of the follicles;blood samples were collected to monitor the concentration of sex hormones(oestradiol and follicle-stimulating hormone).RESULTS The estrous cycles of the model group mice were disrupted throughout the experiment.Mice in the hUCMSC group and the positive control group resumed normal estrous cycles.The ovarian weight of the model group mice continued to decline.The ovarian weight of the hUCMSC group mice and the positive control group mice decreased first and then gradually increased,and the ovarian weight of the hUCMSC group mice was heavier than that of the positive control group mice.The difference was statistically significant(P<0.05).Compared with the negative control group,the model group experienced a decrease in oestradiol and an increase in follicle-stimulating hormone,and the difference was statistically significant(P<0.05).Compared with the model group,the hUCMSC and positive control groups experienced a slight increase in oestradiol and a decrease in follicle-stimulating hormone;the difference was statistically significant(P<0.05).The pathological examination revealed that the mouse ovaries from the model group were atrophied,the volume was reduced,the cortical and medullary structures were disordered,the number of follicles at all stages was significantly reduced,the number of atretic follicles increased,the number of primordial follicles and corpus luteum significantly decreased,and the corpus luteum had an irregular shape.Compared with those of the model group,the lesions of the hUCMSC and positive control groups significantly improved.CONCLUSION hUCMSCs can repair ovarian tissue damaged by chemotherapy to a certain extent,can improve the degree of apoptosis in ovarian tissue,and can improve the endocrine function of mouse ovaries.

Ovarian cancer stem cells: Can targeted therapy lead to improved progression-free survival?

Despite significant effort and research funds, epithelial ovarian cancer remains a very deadly disease. There are no effective screening methods that discover early stage disease; the majority of patients are diagnosed with advanced disease. Treatment modalities consist primarily of radical debulking surgery followed by taxane and platinum-based chemotherapy. Newer therapies including limited targeted agents and intraperitoneal delivery of chemotherapeutic drugs have improved disease-free intervals, but failed to yield longlasting cures in most patients. Chemotherapeutic resistance, particularly in the recurrent setting, plagues the disease. Targeting the pathways and mechanisms behind the development of chemoresistance in ovarian cancer could lead to significant improvement in patient outcomes. In many malignancies, including blood and other solid tumors, there is a subgroup of tumor cells, separate from the bulk population, called cancer stem cells(CSCs). These CSCs are thought to be the cause of metastasis, recurrence and resistance. However, todate, ovarian CSCs have been difficult to identify, isolate, and target. It is felt by many investigators that finding a putative ovarian CSC and a chemotherapeutic agent to target it could be the key to a cure for this deadly disease. This review will focus on recent advances in this arena and discuss some of the controversies surrounding the concept.

Aiming to immune elimination of ovarian cancer stem cells

Ovarian cancer accounts for only 3% of all cancers in women, but it causes more deaths than any other gynecologic cancer. Treatment with chemotherapy and cytoreductive surgery shows a good response to the therapy. However, in a large proportion of the patients the tumor grows back within a few years. Cancer stem cells, that are less responsive to these treatments, are blamed for this recurrence of disease. Immune therapy either cellular or humoral is a novel concept to treat cancer. It is based on the notice that immune cells invade the tumor. However, the tumor invest heavily to escape from immune elimination by recruiting several immune suppressive mechanisms. These processes are normally in place to limit excessive immune activation and prevent autoimmune phenomena. Here, we discuss current knowledge about the immune(suppressive)status in ovarian cancer. Moreover, we discuss the immunological targets of ovarian cancer stem cells.

Human embryonic stem cell-derived mesenchymal stem cells improved premature ovarian failure

BACKGROUND Premature ovarian failure(POF)affects many adult women less than 40 years of age and leads to infertility.According to previous reports,various tissue-specific stem cells can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF.Human embryonic stem cells(ES)provide an alternative source for mesenchymal stem cells(MSCs)because of their similarities in phenotype and immunomodulatory and anti-inflammatory characteristics.Embryonic stem cell-derived mesenchymal stem cells(ES-MSCs)are attractive candidates for regenerative medicine because of their high proliferation and lack of barriers for harvesting tissue-specific MSCs.However,possible therapeutic effects and underlying mechanisms of transplanted ES-MSCs on cyclophosphamide and busulfan-induced mouse ovarian damage have not been evaluated.AIM To evaluate ES-MSCs vs bone marrow-derived mesenchymal stem cells(BMMSCs)in restoring ovarian function in a mouse model of chemotherapy-induced premature ovarian failure.METHODS Female mice received intraperitoneal injections of different doses of cyclophosphamide and busulfan to induce POF.Either human ES-MSCs or BMMSCs were transplanted into these mice.Ten days after the mice were injected with cyclophosphamide and busulfan and 4 wk after transplantation of the ESMSCs and/or BM-MSCs,we evaluated body weight,estrous cyclicity,folliclestimulating hormone and estradiol hormone concentrations and follicle count were used to evaluate the POF model and cell transplantation.Moreover,terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling,real-time PCR,Western blot analysis and immunohistochemistry and mating was used to evaluate cell transplantation.Enzyme-linked immunosorbent assay was used to analyze vascular endothelial growth factor,insulin-like growth factor 2 and hepatocyte growth factor levels in ES-MSC condition medium in order to investigate the mechanisms that underlie their function.RESULTS The human ES-MSCs significantly restored hormone secretion,survival rate and reproductive function in POF mice,which was similar to the results obtained with BM-MSCs.Gene expression analysis and the terminal deoxynucleotidyl transferase mediated 2-deoxyuridine 5-triphosphate nick end labeling assay results indicated that the ES-MSCs and/or BM-MSCs reduced apoptosis in the follicles.Notably,the transplanted mice generated new offspring.The results of different analyses showed increases in antiapoptotic and trophic proteins and genes.CONCLUSION These results suggested that transplantation of human ES-MSCs were similar to BM-MSCs in that they could restore the structure of the injured ovarian tissue and its function in chemotherapy-induced damaged POF mice and rescue fertility.The possible mechanisms of human ES-MSC were related to promotion of follicular development,ovarian secretion,fertility via a paracrine effect and ovarian cell survival.

Presence and role of stem cells in ovarian cancer

Ovarian cancer is the deadliest gynecological malignancy.It is typically diagnosed at advanced stages of the disease,with metastatic sites disseminated widely within the abdominal cavity.Ovarian cancer treatment is challenging due to high disease recurrence and further complicated pursuant to acquired chemoresistance.Cancer stem cell(CSC)theory proposes that both tumor development and progression are driven by undifferentiated stem cells capable of self-renewal and tumor-initiation.The most recent evidence revealed that CSCs in terms of ovarian cancer are not only responsible for primary tumor growth,metastasis and relapse of disease,but also for the development of chemoresistance.As the elimination of this cell population is critical for increasing treatment success,a deeper understanding of ovarian CSCs pathobiology,including epithelial-mesenchymal transition,signaling pathways and tumor microenvironment,is needed.Finally,before introducing new therapeutic agents for ovarian cancer,targeting CSCs,accurate identification of different ovarian stem cell subpopulations,including the very small embryoniclike stem cells suggested as progenitors,is necessary.To these ends,reliable markers of ovarian CSCs should be identified.In this review,we present the current knowledge and a critical discussion concerning ovarian CSCs and their clinical role.

γ-Secretase Inhibitor, DAPT Inhibits Self-renewal and Stemness Maintenance of Ovarian Cancer Stem-like Cells In Vitro

Objective: The Notch signaling pathway plays an important role in the stem cell signaling network and contributes to tumorigenesis. However, the functions of Notch signaling in ovarian cancer stem cells (OCSCs) are not well understood. We aimed to investigate the effects of Notch blockade on self-renewal and stemness maintenance of OCSCs. Methods: Ovarian cancer stem-like cells were enriched from ovarian cancer cell lines in serum-free medium. A γ-secretase inhibitor, (DAPT), was used to block Notch signaling. MTT assays were performed to assess self-renewal and proliferation inhibition, flow cytometry was performed to analyze cell surface marker and immunofluorescence, Western Blot and Real-time RT-PCR assays were performed to detect Oct4 and Sox2 protein and mRNA expression of the Ovarian cancer stem-like cells treated with DAPT. Results: Notch blockade markedly inhibits self-renewal and proliferation of ovarian cancer stem-like cells, significantly downregulates the expression of OCSCs-specific surface markers, and reduces protein and mRNA expression of Oct4 and Sox2 in OCSC-like cells. Conclusion: Our results suggest that Notch signaling is not only critical for the self-renewal and proliferation of OCSCs, but also for the stemness maintenance of OCSCs. The γ-secretase inhibitor is a promising treatment targeting OCSCs.

Application of cattle placental stem cells for treating ovarian follicular cyst

BACKGROUND High humidity and temperature in Taiwan have significant effects on the reproductivity of Holstein cattle,resulting in the occurrence of bovine ovarian follicular cyst(OFC).Because of economic loss from OFC,manual rupture and hormone injection have been advocated for the management of OFC.However,these incomplete treatments increase hormone resistance in cattle.Mesenchymal stem cells(MSCs)derived from placental stem cells(PSCs)demonstrate potential properties for the treatment of several diseases via promoting angiogenesis and immune modulation.AIM To establish the possibility of cattle placental stem cells(CPSCs)as a treatment modality for OFC of cows in Taiwan.METHODS The cows with OFC were divided into three groups:control(BC1 and BC2),hormone(H1 and H2),and CPSC(PS1 and PS2)treatment groups.In the hormone treatment group,the cows were given gonadotrophin-releasing hormone(GnRH)-prostaglandin-GnRH intramuscular injection with or without drainage of follicular fluid.In the CPSC treatment group,CPSCs were isolated from the placenta after labor.With the identification of surface antigen on stem cells,the cows were administered ovarian injection of 1×106 or 6×106 CPSCs with drainage.In all groups,OFC was scanned by ultrasound once a week for a total of seven times.The concentrations of estradiol and progesterone in serum were tested in the same period.The estrus cycle was analyzed by food intake and activity.If estrus was detected,artificial insemination was conducted.Then the cow was monitored by ultrasound for confirmation of pregnancy.RESULTS After 7 d of culture,CPSCs were successfully isolated from placental pieces.CPSCs significantly proliferated every 24 h and had high expression of MSC markers such as cluster of differentiation 44,as determined by flow cytometry.Ultrasound showed lower numbers of OFCs with drainage of follicular fluid.We achieved recovery rates of 0%,50%,50%,75%,75%and 75%in BC1,BC2,H1,H2,PS1,and PS2,respectively.Higher concentrations of progesterone were detected in the CPSC treatment groups.However,both hormone and CPSC treatment groups had no significant difference in the concentration of estradiol.The estrus rate was 0%,100%,25%,75%,75%and 75%in BC1,BC2,H1,H2,PS1,and PS2,respectively.The two fetuses were born in H2 and PS1.In brief,cows with CPSC injection achieved higher recovery,estrus,and inseminated conception rates.CONCLUSION CPSCs have efficacy in treating cows with OFC,and thus,may serve as an alternative treatment for reproductive disorders.

Distinct Side Population Cell Subtypes Have Different Stemness Levels in Human Ovarian Cancer Cells

The stemness of different side population(SP)cell subtypes in ovarian cancer cells was studied,and the heterogeneity of ovarian cancer stem cells was analyzed.The cisplatin-resistant human serous ovarian cancer cell line C13 was stained with the bisbenzimide Hoechst 33342.A flow cytometry-based fluorescence-activated sorting method was used to obtain lower-SP(LSP)cells,upper-SP(USP)cells,and non-SP cells(NSP)based on their sensitivity to the staining time and Hoechst dye concentration.The sphere-forming capability,expression levels of stem cell markers,resistance to high concentrations of cisplatin,and subcutaneous tumorigenicity in NOD/SCID mice of the different cell subtypes were evaluated.The C13 cells contained SP cells with stemness characteristics,and the LSP cell subtype expressed higher levels of stem cell markers,had higher in vitro sphere-forming capability,higher cisplatin resistance and higher in vivo subcutaneous tumorigenesis than USP cells(P<0.05).NSP cells had no stemness.In conclusion,different subtypes of ovarian cancer SP cells have different stemness levels,and ovarian cancer stem cells may be heterogeneous.

An active RUNX1-ID1/ID3 axis governs differentiation and chemoresistance of cancer stem cell population in epithelial ovarian cancer cells

Progression,relapse,and therapy resistance are the most challenging features of cancer therapy that have been postulated to be driven by Cancer Stem Cell(CSC)population.This enigmatic subpopulation of cancer cells has therefore emerged as promising therapeutic candidate.We earlier reported enrichment of CSC-like side population(SP)with increasing resistance towards Cisplatin and Paclitaxel either alone or in combination in epithelial ovarian cancer(EOC)cells.This SP population is a small proportion of the total population of cancer cells characterised with high expression of drug transporters,a unique feature of stem cells and thereby can be isolated through their efflux properties of DNA binding dyes.While the bulk non-SP(NSP)population of the cancer cells lack overexpression of the drug transporters and thus can be identified as the dye containing population.In this study,we show that increased expression of Runt related transcription factor 1(RUNX1)maintains undifferentiated state of CSC-like SP cells through upregulation of inhibitors of DNA binding/differentiation genes(ID1 and ID3)in late cisplatinpaclitaxel resistant cells.Higher RUNX1 expression was found to correlate with decreased median overall survival and disease-free survival in The Cancer Genome Atlas(TCGA)data set of high grade serous ovarian cancer(HGSOC)patients.The protein-protein interaction network analysis of 397 upregulated genes in RUNX1-high samples of TCGA data show significant enrichment of pathways known to negatively regulate CSC differentiation.Intriguingly RUNX1 inhibition not only induces CSC differentiation but also downregulates anti-apoptotic protein BCL2 in both SP and NSP cells and potentiates cytotoxic effects of Cisplatin-Paclitaxel in chemoresistant EOC cells.Inhibition of BCL2 through Venetoclax treatment,a small molecule BH3 mimic,sensitized these cells to platinum taxol treatment.Altogether,our data reveal new regulatory roles by RUNX1 to modulate CSC differentiation via ID1 and ID3 and to promote chemoresistance through BCL2 upregulation.

Extracellular vesicles from iPSC-MSCs alleviate chemotherapy-induced mouse ovarian damage via the ILK-PI3K/AKT pathway

Chemotherapy can significantly reduce follicle counts in ovarian tissues and damage ovarian stroma,causing endocrine disorder,reproductive dysfunction,and primary ovarian insufficiency(POI).Recent studies have suggested that extracellular vesicles(EVs)secreted from mesenchymal stem cells(MSCs)exert therapeutic effects in various degenerative diseases.In this study,transplantation of EVs from human induced pluripotent stem cell-derived MSCs(iPSC-MSC-EVs)resulted in significant restoration of ovarian follicle numbers,improved granulosa cell proliferation,and inhibition of apoptosis in chemotherapy-damaged granulosa cells,cultured ovaries,and in vivo ovaries in mice.Mechanistically,treatment with i PSC-MSC-EVs resulted in up-regulation of the integrinlinked kinase(ILK)-PI3K/AKT pathway,which is suppressed during chemotherapy,most likely through the transfer of regulatory microRNAs(miRNAs)targeting ILK pathway genes.This work provides a framework for the development of advanced therapeutics to ameliorate ovarian damage and POI in female chemotherapy patients.

Expression Compilation of Several Putative Cancer Stem Cell Markers by Primary Ovarian Carcinoma

Cancer stem cells (CSCs) or tumor initiating cells are rare cells that are able to establish a tumor or metastasis. Identification of those CSCs is, however, cumbersome even in established cell lines. Several cancer stem cell markers were reported to be expressed by ovarian cancer. Those cancer stem cells are gifted with lower vulnerability to irradiation and cytostatic drugs explaining the high incidence of recurrence after treatment. A variety of different cancer stem cell markers were described for epithelial tumors. Also, cancer cell lines were assessed for stem cell markers with no common denominator. The expression of CD24, CD44, CD117, CD133, ABCG2, ALDH was determined for cells from 22 patients. Ovarian cancer cells were collected from ascites. Part of the tumor cells were analyzed immediately and stained for the above mentioned cancer stem cell markers. The remainder of the cells was cultured for several weeks using standard stem cell culture conditions. We observed a large variety in expression of putative stem cell markers for primary tumors. After two weeks of culture spheres were seen in several cultures, indicative for cancer stem cells, though not all patients’ cells were able to form spheres. Our data show for the first time the heterogeneity in marker display in primary tumors. Also for the cultured cells stem cell markers were determined. None of the stem cell markers was expressed by all patients’ cells. No correlation with tumor type was demonstrated. The complexity of expression challenges the isolation of cancer stem

Investigation of stem cells in adult and prepubertal mouse ovaries

The possible presence of oocyte and granulosa cells originated from stem cells in the adult mammalian ovaries was claimed by some studies which will lead to major changes in reproductive biology and infertility treatments. Purpose of this research is to investigate the possible existence and the location of the potential stem cells in mouse ovaries. In this study, the ovaries from 2-week (pre-puberty) and 8-week (adult) old BALB-C mice were used. For the investigation of the presence of possible stem cells, the expression profiles of three well known stem cell markers, Oct-4, Nanog and Sox2 were determined in the ovaries of two different age groups by real time quantitative RT-PCR (qRT-PCR). Protein expression levels and their localization in the ovary cells were immunohistochemically evaluated on fresh-frozen ovary tissue sections by using monoclonal antibodies specific to Sox2, Nanog and Oct-4. The gene expression levels of Oct-4 and Nanog were found to be significantly differentiated between 2-week old and 8-week old mice whereas no significant difference was observed in the expression level of Sox2 between two age groups. Immunohistochemistry results showed the presence of both Sox2 and Oct-4 protein in the cytoplasm of ovarian epithelial cells, granulosa cells, oocytes and theca cells. Nanog protein was observed only in the nucleus of the oocytes and furthermore the expression of Nanog was higher in eight weeks old samples compared to two weeks old ones according to qRT-PCR results. These results suggest for the first time that Nanog protein is expressed both in adult and pre-puberty mouse ovaries and locate at the nucleus of the oocytes and to the best of our knowledge this is the first study that shows the differential expression of Oct-4, Nanog and Sox2 in pre-puberty and adult mouse ovaries by qRT-PCR. Collectively, our results may suggest that both pre-puberty and adult mice ovaries accommodate cells carrying stem cell features.

Effects of DC-CIK cell immunotherapy combined with chemotherapy on immune function, coagulation function and tumor stem cell markers in patients with recurrent ovarian cancer

Objective: To investigate the effects of immunotherapy with dendritic cells (DC)-cytokine induced killer cells (CIK) combined with chemotherapy on immune function, coagulation function and tumor stem cell markers in patients with recurrent ovarian cancer. Methods: A total of 80 cases in our hospital for treatment of recurrent ovarian cancer patients were selected as the research object, they were divided into chemotherapy group (n=35) and combined treatment group (n=45) according to whether or not to receive cellular immunotherapy, chemotherapy group received TC chemotherapy, combined therapy group were given DC-CIK cell immunotherapy combined with TC chemotherapy group, the two groups were treated with 21 d for a cycle, 3 cycles were treated;The changes of immune function, coagulation function and tumor stem cell markers were compared between the day of blood collection and the end of treatment for 7 d. Results: After the end of treatment for 7 d, the CD3+, CD3+CD4+, CD4+/CD8+, NK cell number of combined treatment group were significantly higher than that of blood collection day, the number of CD4+ CD25+ was significantly lower than that of blood collection day, The improvement of peripheral blood T lymphocyte subsets in the combined treatment group was better than that in the chemotherapy group;After the end of treatment for 7 d, the FIB levels of two groups were significantly decreased than those of the blood collection day, the difference was statistically significant;After the end of treatment for 7 d, the CD133 and DDX4 levels of two groups were significantly lower than that of the blood collection day, and the combined treatment group was significantly lower than the chemotherapy group, the difference were statistically significant. Results: DC-CIK cell immunotherapy combined with chemotherapy can significantly improve the immunity and the level of FIB of patients with recurrent ovarian cancer, and regulating the level of serum tumor stem cell markers in patients, it has positive significance to improve the prognosis of patients, and is worthy of popularization and application in clinic.

Review of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in solid tumors excluding breast cancer

Solid tumors in adults constitute a heterogeneous group of malignancy originating from various organ systems. Solid tumors are not completely curable by chemotherapy, even though some subgroups are very chemo-sensitive. Recently, oncologists have focused on the use of allogeneic hematopoietic stem cell transplantation(alloHSCT) with reduced intensity conditioning(RIC) for the treatment of some refractory solid tumors. After the demonstration of allogeneic graft-versus-leukemia effect in patients with hematological malignancies who received allo-HSCT, investigators evaluated this effect in patients with refractory metastatic solid tumors. According to data from experimental animal models and preliminary clinical trials, a graft-versus-tumor(GvT) effect may also be observed in the treatment of some solid tumors(e.g., renal cell cancer, colorectal cancer, etc.) after allo-HSCT with RIC. The use of RIC regimens offers an opportunity of achieving full-donor engraftment with GvT effect, as well as, a reduced transplant-related mortality. Current literature suggests that allo-HSCT with RIC might become a choice for elderly and medically fragile patients with refractory metastatic solid tumors.

间充质干细胞来源的外泌体治疗早发性卵巢功能不全的研究进展

早发性卵巢功能不全(POI)是一种常见的妇科疾病,影响许多年轻女性的生活质量和生育能力。临床上常用的激素替代治疗只能暂缓POI患者的症状,无法修复受损的卵巢组织。最近的研究表明,间充质干细胞来源的外泌体在治疗POI中展现出巨大潜力。本文总结了人间充质干细胞来源的外泌体在治疗POI方面的研究进展,为未来在POI诊疗中应用外泌体提供实验基础和相关理论依据。

经血间充质干细胞外泌体对人卵巢癌细胞A2780生物学行为的影响

目的 探讨经血源性间充质干细胞(menstrual blood-derived mesenchymal stem cells,MenSCs)来源的外泌体(MenSCs-derived exosomes,MenSCs-Exos)对人卵巢癌细胞A2780增殖、迁移、侵袭能力和细胞周期分布的影响和机制。方法 分离纯化MenSCs,流式细胞术鉴定其细胞表型,油红O染色观察其成脂分化能力;超速离心法分离MenSCs-Exos,电子显微镜观察外泌体形态,纳米颗粒追踪分析其大小及分布,蛋白免疫印迹法检测外泌体标志性蛋白分子CD9、TSG101、calnexin的表达。采用CCK-8实验、划痕实验、Transwell细胞体外侵袭实验、流式细胞仪检测MenSCs-Exos对A2780细胞增殖、迁移、侵袭能力和细胞周期分布的影响;蛋白免疫印迹法检测Wnt/β-catenin信号通路相关蛋白和迁移相关蛋白的表达。结果 成功分离具有干细胞表型和成脂分化潜能的MenSCs,同时检测发现MenSCs-Exos为边缘清晰、大小分布均匀的膜性囊泡,粒径为30~150 nm,平均为72.89 nm,膜表面标志性蛋白CD9、TSG101表达呈阳性,calnexin表达呈阴性。与对照组相比,MenSCs-Exos能增强A2780细胞增殖、迁移和侵袭能力,影响其细胞周期分布,并且可上调β-catenin、c-Myc、TCF4、Cyclin D1、Vimentin、N-cadherin的表达,下调E-cadherin的表达。结论 MenSCs-Exos可能是通过激活Wnt/β-catenin信号通路促进A2780细胞增殖,并通过下调E-cadherin的表达促进A2780细胞的迁移和侵袭。

干细胞在卵巢组织冷冻与移植中应用的研究进展

干细胞在血液系统疾病中的临床应用已经较为成熟,并进行了广泛推广,例如骨髓造血干细胞移植治疗白血病等,挽救了很多白血病患者的生命。然而,干细胞在生殖医学领域仍处于较慢的初期发展阶段。虽然相对而言,干细胞在卵巢功能障碍的研究已经很多,但在卵巢冷冻与移植上有很多尚未开展且值得研究的方向。本文将从干细胞在卵巢组织冷冻保存和移植方面的最新研究进展进行综述,重点介绍不同来源干细胞改善损伤性卵泡存活的进展及其机制,以及在不孕症治疗和生育能力保存尤其是在卵巢冷冻移植方面的潜在临床应用价值。