Efficacy of Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Animal Model of Female Reproductive Diseases: A Meta-Analysis.

BACKGROUND: Female reproductive disorders, such as premature ovarian insufficiency (POI), intrauterine adhesion (IUA) or thin endometrium, and polycystic ovary syndrome (PCOS), are the main factors affecting fertility. Mesenchymal stem cells derived-extracellular vesicles (MSC-EVs) have gained traction as a new potential treatment and were widely studied in these diseases. However, their impact is still not fully clear. METHODS: A systematic search of PubMed, Web of Science, EMBASE, the Chinese National Knowledge of Infrastructure, and WanFang online databases was performed up to September 27th, 2022, and the studies of MSC-EVs-based therapy on the animal models of female reproductive diseases were included. The primary outcomes were anti-Müllerian hormone (AMH) in POI and endometrial thickness in IUA, respectively. RESULTS: 28 studies (POI, N = 15; IUA, N = 13) were included. For POI, MSC-EVs improved AMH at 2 weeks (SMD 3.40, 95% CI 2.02 to 4.77) and 4 weeks (SMD 5.39, 95% CI 3.43 to 7.36) compared with placebo, and no difference was found when compared with MSCs in AMH (SMD -2.03, 95% CI -4.25 to 0.18). For IUA, MSC-EVs treatment could increase the endometrial thickness at 2 weeks (WMD 132.36, 95% CI 118.99 to 145.74), but no improvement was found at 4 weeks (WMD 166.18, 95% CI -21.44 to 353.79). The combination of MSC-EVs with hyaluronic acid or collagen had a better effect on the endometrial thickness (WMD 105.31, 95% CI 85.49 to 125.13) and glands (WMD 8.74, 95% CI 1.34 to 16.15) than MSC-EVs alone. The medium dose of EVs may allow for great benefits in both POI and IUA. CONCLUSIONS: MSC-EVs treatment could improve the functional and structural outcomes in female reproductive disorders. The combination of MSC-EVs with HA or collagen may enhance the effect. These findings can accelerate the translation of MSC-EVs treatment to human clinical trials.

PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPß signaling and aberrant polarization in decidual macrophages during early spontaneous abortion.

Introduction: Dysregulated macrophage polarization (excessive M1-like or limited M2-like macrophages) in the early decidua contributes to allogeneic fetal rejection and thus early spontaneous abortion. However, the modulators of M1/M2 balance at the early maternal-fetal interface remain mostly unknown. Methods: First-trimester decidual tissues were collected from normal pregnant women undergoing elective pregnancy terminations and patients with spontaneous abortion. We measured the expression of placental growth factor (PlGF) and Fms-like-tyrosine-kinase receptor 1 (FLT-1), and characterized the profiles of macrophages in decidua. Notably, we investigated the effect of recombinant human PlGF (rhPlGF) on decidual macrophages (dMφs) from normal pregnancy and revealed the underlying mechanisms both in vitro and in vivo. Results: The downregulated expression of PlGF/ FLT-1 may result in spontaneous abortion by inducing the M1-like deviation of macrophages in human early decidua. Moreover, the CBA/J×DBA/2 abortion-prone mice displayed a lower FLT-1 expression in uterine macrophages than did CBA/J×BALB/c control pregnant mice. In in vitro models, rhPlGF treatment was found to drive the M2-like polarization of dMφs via the STAT3/CEBPB signaling pathway. These findings were further supported by a higher embryo resorption rate and uterine macrophage dysfunction in Pgf knockout mice, in addition to the reduced STAT3 transcription and C/EBPß expression in uterine macrophages. Discussion: PlGF plays a key role in early pregnancy maintenance by skewing dMφs toward an M2-like phenotype via the FLT-1-STAT3-C/EBPß signaling pathway. Excitingly, our results highlight a rationale that PlGF is a promising target to prevent early spontaneous abortion.

Acetate promotes SNAI1 expression by ACSS2-mediated histone acetylation under glucose limitation in renal cell carcinoma cell.

Metastasis is the main cause of cancer-associated deaths, yet this complex process is still not well understood. Many studies have shown that acetate is involved in cancer metastasis, but the molecular mechanisms remain to be elucidated. In the present study, we first measured the effect of acetate on zinc finger transcriptional repressor SNAI1 and acetyl-CoA synthetase 2 (ACSS2) under glucose limitation in renal cell carcinoma cell lines, 786-O and ACHN. Then, RNA interference and overexpression of ACSS2 were used to detect the role of acetate on SNAI1 expression and cell migration. Finally, chromatin immunoprecipitation assay (ChIP) was used to investigate the regulatory mechanism of acetate on SNAI1 expression. The results showed that acetate increased the expressions of SNAI1 and ACSS2 under glucose limitation. ACSS2 knockdown significantly decreased acetate-induced SNAI1 expression and cell migration, whereas overexpression of ACSS2 increased SNAI1 level and histone H3K27 acetylation (H3K27ac). ChIP results revealed that acetate increased H3K27ac levels in regulatory region of SNAI1, but did not increase ACSS2-binding ability. Our study identified a novel inducer, acetate, which can promote SNAI1 expression by ACSS2-mediated histone acetylation in partly. This finding has important implication in treatment of metastatic cancers.