The effects of human amnion membrane-derived mesenchymal stem cells conditioned medium on ionizing radiation-induced premature ovarian failure and endoplasmic reticulum stress-related apoptosis mechanism.

OBJECTIVES: Premature ovarian failure (POF) is defined as the cessation of menstrual periods for at least 4-6 months before the age of 40 years, accompanied by FSH values measuring over 40 IU/L for a month. Radiation therapy, one of the cancer treatment methods, is known to accelerate ovarian aging by reducing and eliminating the number of primordial follicles in the ovarian follicle pool. Ionizing radiation has been reported to cause POF. The objective of this study is to investigate the impact of mesenchymal stem cell conditioned medium (hAMSCs-CM), which is isolated from the amniotic membrane of human placenta, on premature ovarian failure (POF) caused by whole-body irradiation. The study will focus on the ER stress and apoptosis mechanisms in the process. STUDY DISAYN: A POF model was created by exposing rats to 7 Gy of whole-body irradiation. Serum-free hAMSCs-CM were then administered via the tail vein. Follicle count was performed on the ovaries, and immunohistochemistry was used to determine the expressions of GRP78, CHOP, IRE-1, caspase-12, caspase-9, caspase-3. TUNEL was also carried out, and levels of serum FSH, LH, E2, AMH, and oxidative stress marker 8-OHdG were measured. RESULTS AND CONCLUSION: The application of hAMSCs-CM has been found to have a positive impact on follicles affected by radiation. After treatment, the number of primordial, primary, secondary, and graafian follicles, which had previously decreased due to radiation, showed an increase. Furthermore, the number of atretic follicles, which had been increasing due to radiation, showed a decrease. ER is one of the targets affected by ionizing radiation. After ionizing radiation, the expressions of ER stress-related markers and apoptosis markers increased in the ovary. After hAMSCs-CM administration, the expressions of these markers and number of TUNEL-positive cells decreased. Following irradiation, anti-mullerian hormone (AMH) and estradiol (E2) levels decreased, while follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels increased. After administration of hAMSCs-CM, AMH and E2 levels increased, while FSH and LH levels decreased. Amnion membrane-derived mesenchymal stem cell conditioned medium can play a therapeutic role in ionizing radiation-induced premature ovarian failure by reducing endoplasmic reticulum stress and apoptosis.

Human Amnion Membrane-Derived Mesenchymal Stem Cells and Conditioned Medium Can Ameliorate X-Irradiation-Induced Testicular Injury by Reducing Endoplasmic Reticulum Stress and Apoptosis.

Today, infertility affects 15% of couples and half of this rate is due to reproductive problems in men. Radiation-induced damage to the testicles causes sterility depending on the dose. Radiation causes endoplasmic reticulum (ER) stress and ER stress induces apoptosis. In this study, the effect of human amniotic membrane-derived mesenchymal stem cells (hAMSCs) and conditioned medium (hAMSCs-CM) on testicular damage induced by ionizing radiation is aimed to be elucidated through ER stress and apoptosis mechanisms. Six gray scrotal irradiation was used to create a testicular injury model. hAMSCs isolated and characterized with immunofluorescence and flow cytometry, while 2.5 × 105 hAMSCs were transplanted into testis and hAMSCs-CM was applied. Fertility assessment was performed. Expressions of ER stress markers GRP78, Ire1, Chop and Caspase-12, and Caspase-3 were determined. TUNEL was performed. Serum FSH, LH, and testosterone were measured. After hAMSC transplantation and administration of hAMSCs-CM, offsprings were obtained. Seminiferous tubule diameter and seminiferous epithelial height increased. The expression of GRP78, IRE1α, CHOP, Caspase-12, and Caspase-3 decreased. Percentages of tunel positive cells decreased. While FSH and LH levels decreased, testosterone increased. After irradiation, both hAMSCs transplantation and paracrine activity of hAMSCs may have a role in reducing ER stress by suppressing the UPR response. Decrease in FSH and LH and increase in testosterone level after MSCs transplantation may have contributed to the improvement of spermatogenesis. Thus, it can be said that MSCs derived from human amniotic membrane can improve ionized radiation-induced testicular damage by reducing ER stress and apoptosis.