Human Umbilical Cord Mesenchymal Stem Cells Combined with Dehydroepiandrosterone Inhibits Inflammation-Induced Uterine Aging in Mice.

With the postponement of the reproductive age of women, the difficulty of embryo implantation caused by uterine aging has become a key factor restricting fertility. However, there are few studies on protective interventions for naturally aging uteri. Although many factors cause uterine aging, such as oxidative stress (OS), inflammation, and fibrosis, their impact on uterine function manifests as reduced endometrial receptivity. This study aimed to use a combination of human umbilical cord mesenchymal stem cells (hUC-MSCs) and dehydroepiandrosterone (DHEA) to delay uterine aging. The results showed that the combined treatment of hUC-MSCs + DHEA increased the number of uterine glandular bodies and the thickness of the endometrium while inhibiting the senescence of endometrial epithelial cells. This combined treatment alleviates the expression of OS (reactive oxygen species, superoxide dismutase, and GSH-PX) and proinflammatory factors (interleukin [IL]-1, IL6, IL-18, and tumor necrosis factor-α) in the uterus, delaying the aging process. The combined treatment of hUC-MSCs + DHEA alleviated the abnormal hormone response of the endometrium, inhibited excessive accumulation and fibrosis of uterine collagen, and upregulated uterine estrogen and progesterone receptors through the PI3K/AKT/mTOR pathway. This study suggests that uterine aging can be delayed through hUC-MSCs + DHEA combination therapy, providing a new treatment method for uterine aging.

Application of Human Umbilical Cord Mesenchymal Stem Cells in Rat Spinal Cord Injury Model.

The treatment of spinal cord injury (SCI) is a hot topic in clinic. In this study, female rats were selected and randomly divided into four groups (normal, sham, SCI, and mesenchymal stem cells [MSCs] groups). Hemostatic forceps were used to clamp the spinal cord for 1 min to establish the SCI animal model in rats. The levels of proinflammatory factors in the blood of each group were compared 4 h after operation. The motor function of hind limb was estimated by Basso, Beattie & Bresnahan Locomotor rating scale (BBB scale) at 3 months after surgery, the spinal cord tissue from the experimental area was obtained and stained histologically and immunohistochemically. Basso, Beattie & Bresnahan Locomotor rating scale results indicated that human umbilical cord (HUC) MSCs transplantation could improve the walking ability in rats with the SCI. Human umbilical cord mesenchymal stem cells substantially upregulated the secretion of anti-inflammatory factors and downregulated the secretion of proinflammatory factors, and promoted the repair of the SCI and inhibited the increase of glial cells induced by the SCI. Human umbilical cord mesenchymal stem cells transplantation can partially recovered the motor ability of rats with the SCI through promoting the regeneration of nerve cell and the expression of neural related genes, and inhibiting inflammatory reaction.

Combining Bone Collagen Material with hUC-MSCs for Applicationto Spina Bifida in a Rabbit Model.

Spina bifida is one of the neural tube defects, with a high incidence in human birth defects, which seriously affects the health and quality of life of patients. In the treatment of bone defects, the source of autologous bone is limited and will cause secondary damage to the patient. At the same time, since the bone tissue in animals needs to play a variety of biological functions, its complex structure cannot be replaced by a single material. The combination of mechanical materials and biological materials has become a common choice. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have the advantages of easy access, rapid proliferation, low immunogenicity, and no ethical issues. It is often used in the clinical research of tissue regeneration and repair. Therefore, in this study, we established a spina bifida model using Japanese white rabbits. This model was used to screen the best regenerative repair products for congenital spina bifida, and to evaluate the safety of regenerative repair products. The results showed that the combination of hUC-MSCs with collagen material had better regeneration effect than collagen material alone, and had no negative impact on the health of animals. This study provides a new idea for the clinical treatment of spina bifida, and also helps to speed up the research progress of regenerative repair products.

Combining Bone Collagen Matrix with hUC-MSCs for Application to Alveolar Process Cleft in a Rabbit Model.

BACKGROUND: Most materials used clinically for filling severe bone defects either cannot induce bone re-generation or exhibit low bone conversion, therefore, their therapeutic effects are limited. Human umbilical cord mesenchymal stem cells (hUC-MSCs) exhibit good osteoinduction. However, the mechanism by which combining a heterogeneous bone collagen matrix with hUC-MSCs to repair the bone defects of alveolar process clefts remains unclear. METHODS: A rabbit alveolar process cleft model was established by removing the bone tissue from the left maxillary bone. Forty-eight young Japanese white rabbits (JWRs) were divided into normal, control, material and MSCs groups. An equal volume of a bone collagen matrix alone or combined with hUC-MSCs was implanted in the defect. X-ray, micro-focus computerized tomography (micro-CT), blood analysis, histochemical staining and TUNEL were used to detect the newly formed bone in the defect area at 3 and 6 months after the surgery. RESULTS: The bone formation rate obtained from the skull tissue in MSCs group was significantly higher than that in control group at 3 months (P < 0.01) and 6 months (P < 0.05) after the surgery. The apoptosis rate in the MSCs group was significantly higher at 3 months after the surgery (P < 0.05) and lower at 6 months after the surgery (P < 0.01) than those in the normal group. CONCLUSIONS: Combining bone collagen matrix with hUC-MSCs promoted the new bone regeneration in the rabbit alveolar process cleft model through promoting osteoblasts formations and chondrocyte growth, and inducing type I collagen formation and BMP-2 generation.

Active bone material containing modified recombinant human bone morphogenetic protein-2 induces bone regeneration in rabbit spina bifida.

This study focuses on spina bifida, which is a high incidence among the current clinical manifestations of human birth defects. Because in the treatment of bone defects, the source of autologous bone is limited and it is easy to cause secondary injury to the patient. At the same time, since the bone tissue in animals needs to perform a variety of biological functions, its complex structure cannot be replaced by a single material. Therefore, in this study, we used Japanese white rabbits to establish an animal model similar to human congenital spina bifida. The established animal model is used to screen the best regenerative repair products for the treatment of congenital spondylolisthesis defects, and to evaluate the safety of regenerative repair products. The results show that bone morphogenetic protein (BMP)-2 combined with collagen material has a better regeneration effect than collagen material alone, and it did not negatively affect the health of animals. This study is not only suitable for the screening of large-scale biomaterials, accelerating the research progress of regenerative repair products, but also conducive to the research on the mechanism of regeneration and repair of various materials.

miR-199a Is Upregulated in GDM Targeting the MeCP2-Trpc3 Pathway.

Gestational diabetes mellitus (GDM), the most common medical pregnancy complication, has become a growing problem. More and more studies have shown that microRNAs are closely related to metabolic processes. The purpose of this paper is to investigate the role of up-regulation of miR-199a-5p expression in GDM. We found that miR-199a-5p was significantly up-regulated in the placenta of GDM patients compared with normal pregnant women, and expressed in placental villi. miR-199a-5p can regulate the glucose pathway by inhibiting the expression of methyl CpG-binding protein 2 (MeCP2) and down-regulating canonical transient receptor potential 3 (Trpc3). This suggests that miR-199a-5p may regulate the glucose pathway by regulating methylation levels, leading to the occurrence of GDM.

Genetically engineered FGF1-sericin hydrogel material treats intrauterine adhesion and restores fertility in rat.

Endometrial injury can cause intrauterine adhesions (IUA) and induce the formation of endometrial fibrosis, leading to infertility and miscarriage. At present, there is no effective treatment method for severe IUA and uterine basal injury with adhesion area larger than one-third of the uterus. In this study, we prepared FGF1 silk sericin hydrogel material (FGF1-SS hydrogel) to treat endometrial injury and prevent endometrial fibrosis. Compared with the silk sericin hydrogel material (WT-SS hydrogel), FGF1-SS hydrogel significantly promotes the cell migration and infiltration ability of endometrial stromal cells (ESCs). More importantly, FGF1-SS hydrogel can release FGF1 stably for a long time and inhibit the ESCs injury model forms fibrosis through the TGF-ß/Smad pathway. In the IUA rat model, FGF1-SS hydrogel treatment effectively restored the number of uterine glands and uterine wall thickness in rats, with a fertility rate of 65.1% ± 6.4%. The results show that FGF1-SS hydrogel is expected to be a candidate to prevent IUA.

Transplantation of umbilical cord-derived mesenchymal stem cells promotes the recovery of thin endometrium in rats.

The endometrium plays a critical role in embryo implantation and pregnancy, and a thin uterus is recognized as a key factor in embryo implantation failure. Umbilical cord mesenchymal stem cells (UC-MSCs) have attracted interest for the repair of intrauterine adhesions. The current study investigated the repair of thin endometrium in rats using the UC-MSCs and the mechanisms involved. Rats were injected with 95% ethanol to establish a model of thin endometrium. The rats were randomly divided into normal, sham, model, and UC-MSCs groups. Endometrial morphological alterations were observed by hematoxylin-eosin staining and Masson staining, and functional restoration was assessed by testing embryo implantation. The interaction between UC-MSCs and rat endometrial stromal cells (ESCs) was evaluated using a transwell 3D model and immunocytochemistry. Microarray mRNA and miRNA platforms were used for miRNA-mRNA expression profiling. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed to identify the biological processes, molecular functions, cellular components, and pathways of endometrial injury and UC-MSCs transplantation repair and real-time quantitative reverse transcription PCR (qRT-PCR) was performed to further identify the expression changes of key molecules in the pathways. Endometrium thickness, number of glands, and the embryo implantation numbers were improved, and the degree of fibrosis was significantly alleviated by UC-MSCs treatment in the rat model of thin endometrium. In vitro cell experiments showed that UC-MSCs migrated to injured ESCs and enhanced their proliferation. miRNA microarray chip results showed that expression of 45 miRNAs was downregulated in the injured endometrium and upregulated after UC-MSCs transplantation. Likewise, expression of 39 miRNAs was upregulated in the injured endometrium and downregulated after UC-MSCs transplantation. The miRNA-mRNA interactions showed the changes in the miRNA and mRNA network during the processes of endometrial injury and repair. GO and KEGG analyses showed that the process of endometrial injury was mainly attributed to the decomposition of the extracellular matrix (ECM), protein degradation and absorption, and accompanying inflammation. The process of UC-MSCs transplantation and repair were accompanied by the reconstruction of the ECM, regulation of chemokines and inflammation, and cell proliferation and apoptosis. The key molecules involved in ECM-receptor interaction pathways were further verified by qRT-PCR. Itga1 and Thbs expression decreased in the model group and increased by UC-MSCs transplantation, while Laminin and Collagen expression increased in both the model group and MSCs group, with greater expression observed in the latter. This study showed that UC-MSCs transplantation could promote recovery of thin endometrial morphology and function. Furthermore, it revealed the expression changes of miRNA and mRNA after endometrial injury and UC-MSCs transplantation repair processed, and signaling pathways that may be involved in endometrial injury and repair.

Effects of single and multiple transplantations of human umbilical cord mesenchymal stem cells on the recovery of ovarian function in the treatment of premature ovarian failure in mice.

BACKGROUND: Currently, there is no effective treatment for premature ovarian failure (POF), and stem cell therapy is considered the most promising treatment. Human umbilical cord blood mesenchymal stem cells (hUC-MSCs) have shown good regenerative ability in various diseases, including POF; however, their underlying mechanism and dosage for POF treatment remain unclear. This study aimed to compare the effect of single and multiple injections of hUC-MSCs on ovarian function repair in chemotherapy-induced POF. METHODS: Female mice were intraperitoneally injected with 30 mg/kg busulfan and 120 mg/kg cyclophosphamide (CTX) to induce POF. In the single hUC-MSC injection group, hUC-MSCs were transplanted into mice D7 after CTX and busulfan administration, while in the multiple injection group, hUC-MSCs were transplanted on D7, D14, and D21 after CTX and busulfan administration. We evaluated the ovarian morphology, fertility, follicle-stimulating hormone and estradiol concentrations, follicle count, POF model, and cell transplantation results. In addition, real-time polymerase chain reaction, immunohistochemistry, and miRNA and mRNA chips were used to evaluate the effect of the cell therapy. RESULTS: Ovary size, number of follicle at all developmental stages, and fertility were significantly reduced in the POF group compared with the control. Under hUC-MSC treatment, the ovarian morphology and follicle count were significantly restored, and fertility was significantly increased. By comparing the single and multiple hUC-MSC injection groups, we found that the anti-Müllerian hormone and Ki-67 levels were significantly increased in the multiple hUC-MSC group on D60 after chemotherapy. The expression of stimulating hormone receptors, inhibin α, and inhibin ß was significantly restored, and the therapeutic effect was superior to that of the single hUC-MSC injection group. CONCLUSION: These results indicate that hUC-MSCs can restore the structure of injured ovarian tissue and its function in chemotherapy-induced POF mice and ameliorate fertility. Multiple hUC-MSC transplantations have a better effect on the recovery of ovarian function than single hUC-MSC transplantation in POF.

Repair of alveolar cleft bone defects in rabbits by active bone particles containing modified rhBMP-2.

Objective: A model of alveolar cleft phenotype was established in rabbits to evaluate the effect of active bone particles containing modified rhecombinant human BMP-2 on the repair of the alveolar cleft. Methods: 2-month-old Japanese white rabbits were selected and randomly divided into four groups: normal, control, material and BMP groups. Blood biochemical analysis, skull tomography (microfocus computerized tomography), and histological and immunohistochemical staining analysis of paraffin sections were performed 3  and 6 months after operation. Results: Both types of collagen particles showed good biocompatibility and promoted bone regeneration. The effect of active bone particles on bone repair and regeneration was better than that of bone collagen particles. Conclusions: Active bone particles containing modified rhecombinant human BMP-2 can be used for incisors regeneration.

Homocysteine-induced neural tube defects in chick embryos via oxidative stress and DNA methylation associated transcriptional down-regulation of miR-124.

Although moderate homocysteine (HCY) elevation is associated with neural tube defects (NTDs), the underlying mechanisms have not been elucidated. In this study, we aimed to investigate that whether HCY-induced NTDs were associated with oxidative stress and methyl metabolism in chick embryos. The potential role of miR-124 in neurogenesis was also investigated. In this study, increased intracellular oxidative species and alterations in DNA methylation were observed following HCY treatment. This alteration coincided with decreases of Mn superoxide dismutase and glutathione peroxidase activities, as well as the expression of anti-rabbit DNA methyltransferase (DNMT) 1 and 3a. In addition, HCY induced significant decreases of S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) (P < 0.05). N-acetyl-L-cysteine and choline ameliorated global DNA hypomethylation induced by HCY. MiR-124 levels were significantly suppressed by HCY (P < 0.05), while elevated by 5-aza-2'-deoxycytidine (5-aza-dC). MiR-124 knockdown resulted in spina bifida occulta. Our research suggests that HCY-induced NTDs were associated with oxidative stress and methyl metabolism in chick embryos. MiR-124 down-regulation may occur via epigenetic mechanisms and contribute to HCY-induced NTDs in chick embryo models.

Down-regulation of microRNA-30d-5p is associated with gestational diabetes mellitus by targeting RAB8A.

Gestational Diabetes Mellitus (GDM) is a complicated clinical process, and metabolic disorders during pregnancy are closely related to the structure and function of the placenta. The aberrant expression of miRNAs in the placenta may play a role in the occurrence and development of GDM. Analysis of microRNA (miRNA) expression signature in placenta showed that the level of miR-30d-5p was significantly down-regulated in GDM patients. This study aims to explore the possible mechanism of GDM under the regulation of miR-30d-5p. In situ hybridization and qRT-PCR assay showed that miR-30d expression down-regulated in the placentas from GDM patients compared with normal control group. The trophoblast cells proliferation and glucose uptake capacity were increased, the ability of migration and invasion were also improved after inhibiting the function of endogenous mature miR-30d-5p. Bioinformatics analysis and luciferase reporter assays showed that miR-30d-5p binds to the 3'UTR of RAB8A mRNA, resulting in RAB8A suppression. Moreover, the down-regulation of RAB8A could attenuate the increase in trophoblast cell proliferation, migration, invasion and glucose uptake induced by miR-30d-5p functional inhibitor. These data imply that miR-30d-5p expression is down-regulated in placental tissue from GDM patients and affects trophoblast cell functions by targeting RAB8A, which may provide new insight into the pathogenesis of GDM.

Active bone material containing modified recombinant human bone morphogenetic protein 2 induces bone regeneration in the alveolar process cleft in rabbits.

The clinical application of most materials used to fill severe bone defects is limited owing to the insufficient ability of such materials to induce bone regeneration over a long repair period. The purpose of this study was to establish a model for the alveolar process cleft in rabbits to evaluate the effect of active bone material in bone defect repair. The active bone material used in this study is a new bone repair material composed of a heterogeneous collagen membrane implanted with modified recombinant human bone morphogenetic protein 2. This proposed active bone material can specifically bind to collagen. Twenty-four young Japanese white rabbits (JWRs) were selected and randomly divided into four groups (normal, control, material, and bone morphogenetic protein groups). The alveolar process cleft model was established by removing an equal volume bone at the left maxillary position. Blood samples were collected from the JWRs 3 and 6 months after the surgery to evaluate the biocompatibility of the active bone materials. Subsequently, the skull model was established, and the appearance was observed. Imaging methods (including X-ray examination and micro-computerized tomography scanning), tissue staining, and immunohistochemistry were employed for the evaluation. The bone collagen material and active bone material exhibited high biocompatibility. In addition, the ability of the active bone material to induce bone repair and regeneration was higher than that of the bone collagen material. The active bone material exhibited satisfactory bone regeneration performance in rabbits, indicating its potential as an active material for repairing congenital alveolar process clefts in humans.

Diethylhexyl phthalate induces teratogenic effects through oxidative stress response in a chick embryo model.

Diethylhexyl phthalate (DEHP) is known as a persistent environmental pollutant. However, the possible effects of DEHP on human neural tube defects (NTDs) remain elusive. We set out to investigate the exposure of DEHP in human and explore the association of DEHP and NTDs. The level of DEHP in maternal urine was measured and analyzed by GC-MS. To further validate the results in human NTDs, chick embryos were used as animal models. Viability, reactive oxygen species (ROS) level, oxidative stress indicators and apoptosis were detected in DEHP-treated chick embryos. Our research revealed that the detection ratio of positive DEHP and its metabolites in maternal urine were observed dramatically higher in NTDs population than that in normal controls (P < 0.01, P < 0.05, respectively). Moreover, DEHP treatment (10-6 M) led to developmental toxicity in chick embryos via accelerating oxidative stress response and cell apoptosis, and changing the level of oxidative stress-related indicators. Moreover, high dose choline (100 µg/µl) could partially restrain the toxicity effects induced by DEHP. Our data collectively imply that the incidence of NTDs may closely associate with DEHP exposure, which disturbs the development of neural tubes by enhancing oxidative stress.

Down-Regulated miR-21 in Gestational Diabetes Mellitus Placenta Induces PPAR-α to Inhibit Cell Proliferation and Infiltration.

PURPOSE: This study aimed to investigate the role of miR-21 expression in the reduction of placental function in GDM patients. MATERIALS AND METHODS: qRT-PCR was used to detect the differential expression of miR-21 in the serum of gestational diabetes mellitus (GDM) and normal pregnant women, and to verify the functional target gene PPAR-α of miR-21 by double fluorescence experiments. Cellular experiments were performed to verify the effect of PPAR-α on cell function. RESULTS: miR-21 is down-regulated in the serum and placenta of GDM patients compared to normal pregnant women. In the case of insulin resistance, miR-21-5p knockdown promoted glucose uptake, but no significant effect was found under physiological condition. Functional studies have shown that reduced PPAR-α expression can restore miR-21 knockdown-mediated cell growth and metastasis inhibition. Additionally, decreased expression of miR-21 but increased expression of -PPAR-α was observed in patients with GDM and GDM rats. CONCLUSION: The expression of the placental miR-21-5p, which inhibits cell growth and infiltration by up-regulating PPAR-α, is downregulated in pregnant GDM patients, which in turn may affect the placental function.

Repair of alveolar cleft bone defects by bone collagen particles combined with human umbilical cord mesenchymal stem cells in rabbit.

BACKGROUND: Alveolar cleft is a type of cleft lip and palate that seriously affects the physical and mental health of patients. In this study, a model of the alveolar cleft phenotype was established in rabbits to evaluate the effect of bone collagen particles combined with human umbilical cord mesenchymal stem cells (HUC-MSCs) on the repair of alveolar cleft bone defects. METHODS: A model of alveolar clefts in rabbits was established by removing the incisors on the left side of the upper jaw bone collagen particles combined with HUC-MSCs that were then implanted in the defect area. Blood biochemical analysis was performed 3 months after surgery. Skull tissues were harvested for gross observation, and micro-focus computerised tomography (micro-CT) analysis. Tissues were harvested for histological and immunohistochemical staining. The experiments were repeated 6 months after surgery. RESULTS: Bone collagen particles and HUC-MSCs showed good biocompatibility. Bone collagen particles combined with HUC-MSCs were markedly better at inducing bone repair and regeneration than bone collagen particles alone. CONCLUSIONS: Combining HUC-MSCs with bone collagen particles provides a simple, rapid and suitable method to fill a bone defect site and treat of alveolar cleft bone defects.

Oxidative stress response associates with the teratogenic effects of benzyl butyl phthalate (BBP).

Benzyl butyl phthalate (BBP) is a persistent environmental pollutant. BBP exposure and the possible effects on human neural tube defects (NTDs) remain elusive. In this study, we found that the detection ratio of positive BBP and its metabolites in maternal urine was obviously higher in NTDs' population than that in normal controls by GC-MS (P < 0.01, P < 0.05, respectively). Animal experiments showed that BBP treatment induced developmental toxicity in chick embryo by enhancing the levels of oxidative stress and cell apoptosis (P < 0.01). More interestingly, the supplement of high-dose choline (CHO, 10 5  µg/mL) could partially restore the teratogenic effects of BBP by inhibiting the occurrence of oxidative stress. Our data collectively suggest that BBP exposure may disturb neural tube development by strengthening oxidative stress. CHO can partially restore the toxicity effects of BBP. This study may provide new insight for NTD prevention.

The miRNA-29b Is Downregulated in Placenta During Gestational Diabetes Mellitus and May Alter Placenta Development by Regulating Trophoblast Migration and Invasion Through a HIF3A-Dependent Mechanism.

Gestational diabetes mellitus (GDM) is a disease that changes the function of microvascular of placenta. MicroRNA (miRNA) expression in placenta may contribute to the pathogenesis of GDM. Here, we evaluate the role and function of miR-29b in the development of GDM. This study discovered that miR-29b expression was lower in placentas derived from patients with GDM than that in control placentas. MiR-29b over-expression inhibited cell growth and migration, and miR-29b knockdown promoted cell migration. Then we predicted and confirmed that HIF3A was a direct target of miR-29b with two specific binding sites at the recognition sequences of miR-29b in 3'-UTR of HIF3A mRNA, which was negatively correlated with miR-29b expression level. The up-regulation of HIF3A partially antagonized the inhibitory effect of miR-29b over-expression on cell growth and migration. The enhancement of cell migration induced by miR-29b knockdown was attenuated by down-regulating HIF3A. These results imply that down-regulation of miR-29b may be related with the development of GDM partially via increasing the expression of HIF3A, which may provide a new insight for the mechanism of GDM.

miR-98 is involved in missed abortion by targeting GDF6 and FAPP2.

Missed abortion (MA) is a common disease in obstetrics and gynecology. More and more studies have focused on the relationship between miRNAs and pregnancy maintenance and its related diseases. The aim of this article is to explore the relationship between miRNA and MA. The expression of miR-98 were detected by in situ hybridization and real-time PCR. Cell proliferation, activity and migration were measured via Edu, MTT, and transwell assays. The target genes of miR-98 are identified by dual-luciferase activity assay. And the expression levels of target genes were determined by Western blot, real-time PCR and immunohistochemistry. miR-98 was significantly up-regulated in placental villi from over 35 years old MA patients compared with the age-matched normal pregnant women. Up-regulation of miR-98 suppressed the proliferation, activity and migration of the human trophoblast HTR-8/SVneo cell in vitro. miR-98 could bind to GDF6 and FAPP2 mRNA 3'-UTR and negatively regulate their expression. The downregulation of miR-98 promoted cell proliferation, then knockdown of GDF6 or FAPP2 inhibited miR-98-mediated cell proliferation. GDF6 and FAPP2 expression in the placental villi from MA patients were decreased compared to normal placental tissues. The expression of miR-98 in MA had an opposite relationship with the expression of GDF6 and FAPP2. Overexpression of miR-98 is associated with the occurrence of MA. miR-98 prevents proliferation, viability and migration of trophoblast cells partially through targeting GDF6 and FAPP2.

MiR-93 Inhibits Trophoblast Cell Proliferation and Promotes Cell Apoptosis by Targeting BCL2L2 in Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion (RSA) is a common health problem that affects 1-5% of women in reproductive age. Plenty of studies have indicated that microRNAs (miRNAs) are involved in the occurrence of miscarriage. MiR-93 has a wide range of functions in mammalian tissues and plays an important role in many diseases especially for cancers. However, it remains unknown whether miR-93 is associated with human RSA. In this report, clinical samples revealed that miR-93 expression was significantly elevated in the villi tissues of RSA patients. Upregulation of miR-93 inhibited human trophoblast cells HTR-8/SVneo cell proliferation, migration, and invasiveness, but promoted cell apoptosis in vitro. Conversely, the downregulation of miR-93 reversed these effects. Bcl-2 like protein 2 (BCL2L2), a potential target gene of miR-93, was inversely correlated with miR-93 expression in the villi of clinical samples. Furthermore, the luciferase reporter system demonstrated that miR-93 directly downregulated the expression of BCL2L2 by binding a specific sequence of its 3'-untranslated region (3'UTR). Collectively, these data strongly suggest that miR-93 regulates trophoblast cell proliferation, migration, invasive, and apoptosis by targeting BCL2L2 expression and is involved in the pathogenesis of RSA.