Therapeutic effects of human umbilical cord mesenchymal stem cell-derived microvesicles on premature ovarian insufficiency in mice

Abstract

Background Premature ovarian insufficiency (POI) is one of the leading causes of female infertility, which is caused by an abnormal ovarian reserve. Currently, there is no effective treatment to restore the fertility of POI patients. Recent studies suggested that microvesicles (MVs) released from mesenchymal stem cells (MSCs) exert therapeutic effects in various degenerative diseases. In this study, the effect of human umbilical cord MSC-derived MVs (HUCMSC-MVs) on the restoration of ovarian function in a chemotherapy-induced POI mouse model is investigated. Methods MVs were obtained from the supernatant of cultured HUCMSCs. The localization of PKH26-labeled HUCMSC-MVs in ovarian tissues was observed by confocal laser scanning microscopy. Histomorphometric analysis was performed to count the number of ovarian follicles and vessels. The ovarian sections were stained with anti-CD34 to evaluate angiogenesis. The levels of estradiol (E2) and follicle-stimulating hormone (FSH) were measured by enzyme-linked immunosorbent serologic assay. The mRNA expression of angiogenesis-related cytokines and the protein expression of AKT in mouse ovaries were measured by quantitative RT-PCR and western blot analysis. The parametric variables were compared by Student’s t test and analysis of variance. The non-parametric variables were compared by the Mann-Whitney U test. Categorical variables were compared by χ 2 test. P < 0.05 was considered statistically significant. Results PKH26-labeled HUCMSC-MVs were detectable within the ovaries and migrated to the ovarian follicles 24 h after transplantation. The transplantation of HUCMSC-MVs could increase the body weight and number of ovarian follicles (primordial, developing, and preovulatory follicles), induce ovarian angiogenesis, and recover the disturbed estrous cycle of POI mice. The expression levels of total AKT, p-AKT, and angiogenic cytokines (including VEGF, IGF, and angiogenin) in the ovaries of POI mice were markedly upregulated after HUCMSC-MVs transplantation, suggesting that HUCMSC-MVs transplantation might recover ovarian function by inducing angiogenesis via the PI3K/AKT signaling pathway. Conclusions This study provides valuable insight into the effects of HUCMSC-MVs on ovarian tissue angiogenesis and on the restoration of ovarian function in POI mice, which may be helpful to develop a treatment strategy for POI patients.

Exosomal miRNA-17-5p derived from human umbilical cord mesenchymal stem cells improves ovarian function in premature ovarian insufficiency by regulating SIRT7

“…Consistent with our findings, hUMSCs and hUMSC-Exos have been reported to preserve ovarian function in POI mice. 12,15,18,20 Previous studies have also reported that exosomes from human adipose MSCs and amniotic fluid stem cells can restore ovarian function after CTX-induced damage. 18,20 In addition, the expression levels of SIRT7 and its candidate downstream target genes were downregulated after hUMSC-Exos treatment in this study.…”

“…12,13 One of the key mechanisms of MSC-induced therapeutic effects is the paracrine activity of secreted factors, which are mediated by extracellular vesicles (EVs). 10,14,15 Among the many subtypes of EVs, exosomes are considered to be powerful cell-to-cell communicationrelevant components of the MSC secretome with low immunogenicity and tumorigenicity. 16,17 Exosomes released from hUMSCs (hUMSC-Exos) are reported to suppress ovarian granulosa cell apoptosis and regulate the immune response.…”

hUCMSC-extracellular vesicles downregulated hepatic stellate cell activation and reduced liver injury in S. japonicum-infected mice

“…Indeed, EVs contain a subset of proteins, lipids, and nucleic acids derived from the donor cell and play important roles in intercellular communication through transferring their contents, including proteins, lipids, and RNAs, between cells [13]. EVs produced by MSCs (MSC-EVs) exert therapeutic effects in several disease models such as chemotherapy-induced mouse model of premature ovarian failure [14], experimental allergic asthma [15], and Escherichia coli endotoxin-induced acute lung injury [16]. In addition, EVs have reduced potential side effects because they are less complex and better defined as compared to MSC therapies, and there are additional logistical advantages of using EVs, which can be considered as an off-the-shelf product.…”

Extracellular Vesicles Derived from Mesenchymal Stem Cells Recover Fertility of Premature Ovarian Insufficiency Mice and the Effects on their Offspring

“…Furthermore, previous studies evaluate the safety of human umbilical cord mesenchymal stem cells (HUCMSCs) derived EVs on liver or renal function 14 , but no study investigates whether the treatment of EVs to women of child-bearing age will influence the development of their offspring. Recently, Yang et al 15 found that EVs derived from HUCMSCs could locate in ovarian tissue after transplantation and play essential roles in promoting ovarian angiogenesis and restoring ovarian function of POI mice. However, they neither evaluate the fertility of the POI mice nor the influence on their offspring after EVs transplantation, which is of great concern for a new treatment for women with POI who desire to have a child.…”