Myung Joo Kim

The maturation of the oocyte is influenced by cumulus cells (CCs) and associated with pregnancy rate, whereas the influencing factors have not been completely elucidated in the CCs. In this study, we identified new regulators of CCs for high-quality oocytes and successful pregnancies during assisted reproductive techniques. CCs were collected from cumulus–oocyte complexes (COCs) in young (≤33 years old) and old (≥40 years old) women undergoing intracytoplasmic sperm injection (ICSI) procedures. We screened for factors differentially expressed between young vs. old CCs and pregnancy vs. non-pregnancy using whole mRNA-seq-next-generation sequencing (NGS). We characterized the transcriptome of the CCs to identify factors critical for achieving pregnancy in IVF cycles. Women in the young and old pregnancy groups exhibited the up- and downregulation of multiple genes compared with the non-pregnancy groups, revealing the differential regulation of several specific genes involved in ovarian steroidogenesis in CCs. It was shown that the low-density lipoprotein (LDL) receptor to the steroidogenesis pathway was upregulated in CCs with higher maturity rates of oocytes in the pregnancy group. In conclusion, a higher pregnancy rate is related to the signaling pathway of steroidogenesis by the LDL receptor in infertile women undergoing IVF procedures.

Inflammation is a major cause of several chronic diseases and is reported to be recovered by the immuno-modulation of mesenchymal stem cells (MSCs). While most studies have focussed on the anti-inflammatory roles of MSCs in stem cell therapy, the impaired features of MSCs, such as the loss of homeostasis by systemic aging or pathologic conditions, remain incompletely understood. In this study, we investigated whether the altered phenotypes of human placenta-derived MSCs (hPD-MSCs) exposed to inflammatory cytokines, including TNF-α and IFN-γ, could be protected by MIT-001, a small anti-inflammatory and anti-necrotic molecule. MIT-001 promoted the spindle-like shape and cytoskeletal organization extending across the long cell axis, whereas hPD-MSCs exposed to TNF-α/IFN-γ exhibited increased morphological heterogeneity with an abnormal cell shape and cytoskeletal disorganization. Importantly, MIT-001 improved mitochondrial distribution across the cytoplasm. MIT-001 significantly reduced basal respiration, ATP production, and cellular ROS levels and augmented the spare respiratory capacity compared to TNF-α/IFN-γ-exposed hPD-MSCs, indicating enhanced mitochondrial quiescence and homeostasis. In conclusion, while TNF-α/IFN-γ-exposed MSCs lost homeostasis and mitochondrial quiescence by becoming over-activated in response to inflammatory cytokines, MIT-001 was able to rescue mitochondrial features and cellular phenotypes. Therefore, MIT-001 has therapeutic potential for clinical applications to treat mitochondrion-related inflammatory diseases.

Current therapeutic medicines for endometriosis cannot be administered during assisted reproductive technology (ART) because they have bad effects during pregnancy. In this study, we created an animal model of endometriosis and evaluated the therapeutic effect of progestin (Dienogest), dopamine agonist (Cabergoline), and their combination (Dienogest + Cabergoline). We established a mouse model mimicking human endometriosis. The mice with endometriosis were then treated with a single drug (Dienogest or Cabergoline) or both drugs (Dienogest + Cabergoline) for 14 days. An immunohistological study was then performed to analyze inflammatory lesions in the recipient mice. Real-time polymerase chain reaction (RT-PCR) and Western blotting were also performed to determine the levels of genes and proteins in inflammatory lesions to assess the recovery of endometriosis. Histologic staining showed that all medication groups showed a clear decrease in the inflammatory phenotype in the uterus, peritoneum, and intestine. Gene and protein expression analysis showed a therapeutic effect in all medication groups. In conclusion, Cabergoline had a therapeutic effect similar to that of Dienogest and could be used as an alternative to Dienogest during ART for patients with infertility; compared to the individual drugs, the combination treatment has a synergistic effect on endometriosis.