Journal Article

Placental-Derived Mesenchymal Stem Cells Triggers Lipid Metabolism in a Rat Model Thioacetamide-Induced Ovarian Disease via Increased CPT1A Expression for Mitochondrial Dynamics

Seok, Jin, Kim, Gi Jin, Park, Hyeri, Lee, Hankyu, Lee, Dae Hyun, You, Jun Hyeong

2025

Overview

Lipid accumulation disrupts mitochondrial dynamics, leading to dysfunctional energy metabolism and increased oxidative stress. However, the relationship between mitochondrial dynamics and ovarian function in therapeutic contexts is still not fully elucidated. Therefore, the objective of this study was to demonstrate whether increased carnitine palmitoyltransferase 1A (CPT1A) expression induced by placenta-derived mesenchymal stem cells (PD-MSCs) improves ovarian function in ovaries of a lipid toxicity-induced rat model by regulating lipid metabolism and mitochondrial dynamics. A rat model of injury was induced through intraperitoneal administration of thioacetamide (TAA) for 12 weeks. During the 8th week of induction, PD-MSCs (2 × 10 cells) were transplanted via the tail vein. Initially, we examined the engraftment of PD-MSCs. The inflammatory response (e.g., IL-6, TNFα) and apoptosis (e.g., LDH levels, TUNEL assay) were significantly increased in the non-transplanted (NTx) group compared to the normal group; however, they were significantly decreased in the transplanted (Tx) group compared to the NTx group (* < 0.05). Additionally, oxidative stress was attenuated through the regulation of mitochondrial dynamics, including the expression of DRP1, ATP5B, and PGC1α, in the Tx group compared to the NTx group (* < 0.05). In the NTx group, abnormally accumulated lipid droplets were observed due to dysfunctional mitochondria, whereas in the Tx group, the accumulation of lipid droplets and the expression of CPT1A were significantly comparable to those in the normal group (* < 0.05). The levels of the steroidogenesis markers (e.g., CYP11A1 and HSD3β1) were decreased in the NTx group compared to the normal group and increased in the Tx group compared to the NTx group (* < 0.05). The levels of sex hormone and follicular development were protected in the Tx group compared to the NTx group. Furthermore, cocultivation of PD-MSCs with etomoxir (CPT1A inhibitor)-treated primary theca cells increased the expression of steroidogenesis. In conclusion, PD-MSCs improve ovarian function in TAA-induced injury by reducing lipid accumulation and oxidative stress through the regulation of lipid metabolism and mitochondrial dynamics. The upregulation of CPT1A and related mitochondrial proteins contributes to enhanced steroidogenesis and restoration of ovarian homeostasis. These findings offer new insights into the application of stem cell therapies for reproductive medicine.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Androgens / Animals / Apoptosis / Carnitine O-Palmitoyltransferase - metabolism / Carnitine palmitoyltransferase / Cell culture / Cell therapy / Disease / Disease Models, Animal / Embryos / Energy metabolism / Estrogens / Fatty acids / Female / Follicles / Glucose / Homeostasis / Hormone replacement therapy / Inflammation / Insulin resistance / Laboratory animals / Lipid Metabolism / Lipid peroxidation / Lipids / Menstruation / Mesenchymal Stem Cell Transplantation / Mesenchymal stem cells / Mesenchymal Stem Cells - cytology / Mesenchymal Stem Cells - metabolism / Metabolism / Mitochondria / Mitochondria - metabolism / mitochondria dynamics / Mitochondrial Dynamics / Ovarian Diseases - chemically induced / Ovarian Diseases - metabolism / Ovarian Diseases - pathology / Ovarian Diseases - therapy / ovarian dysfunction / Ovaries / Ovulation / Oxidation / Oxidative metabolism / Oxidative Stress / Palmitoyltransferase / Placenta - cytology / placenta-derived mesenchymal stem cell / Polycystic ovary syndrome / Pregnancy / Rats / Rats, Sprague-Dawley / Reproductive status / Sex hormones / Stem cells / Steroidogenesis / Theca / Thioacetamide / Toxicity