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Dose-dependent efficacy of human placenta-derived mesenchymal stem cell transplantation on antioxidant effects in an ovariectomized rat model.
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Written by: Jin SeokJin Seok SciProfiles Scilit Preprints.org Google Scholar 1, Hyeri ParkHyeri Park SciProfiles Scilit Preprints.org Google Scholar 1, 2, Dae-Hyun LeeDae-Hyun Lee SciProfiles Scilit Preprints.org Google Scholar 1, 2 June Hyun Hyun You SciProfiles Scilit Preprints.org Google Scholar 1 and Gi Jin KimGi Jin Kim SciProfiles Scilit Preprints.org Google Scholar 1, 2, *
Date Submitted: July 4, 2023 / Date Revised: July 26, 2023 / Date Received: August 3, 2023 / Date Published: August 7, 2023
Oxidative stress initiates several degenerative diseases and is caused by excessive production of reactive oxygen species (ROS). Oxidative stress is a major contributing factor to infertility by causing ovarian dysfunction characterized by dysregulated hormone levels, poor quality of mature follicles, and loss of follicles. Therefore, stem cell therapy is being actively investigated as an approach to overcome the side effects of hormone replacement therapy (HRT) in ovarian dysfunction. However, there is a lack of evidence regarding the appropriate number of cells required for stem cell therapy. Therefore, based on the antioxidant effects investigated in this study, we focused on determining the appropriate dose of stem cells for transplantation in an animal model of ovarian dysfunction. Placenta-derived mesenchymal stem cells (PD-MSCs, 1 × 10) one week after ovariectomy
Cells) injected into the Tx group via the tail vein. As a result, the mRNA expression of HAlu gradually increased as the number of transplanted cells increased. Compared to no transplantation (NTx), PD-MSC transplantation improved folliculogenesis, including the level of secreted hormones and the number of follicles, by exerting an antioxidant effect. In addition, the level of oxidized glutathione in the serum of the post-transplant animal model increased significantly (* p < 0.05). These results showed that PD-MSC transplantation improved ovarian function by exerting an antioxidant effect in hemi-ovarianized rats. According to our data, an increase in the number of transplanted cells disproportionately increases the effectiveness of the treatment. We propose that low-dose PD-MSC transplantation will have the same therapeutic effect as described in previous studies. These findings provide new information to better understand the reproductive system and provide evidence for relevant clinical studies.
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Reactive oxygen species (ROS) are produced by various factors and are molecular signals that regulate physiological and biological processes. ROS are strongly associated with damage to lipids, proteins, and DNA and are a major cause of oxidative stress; ROS include superoxide anion, hydrogen peroxide, and hydroxyl radicals. H. is
Neutralization through the protective mechanism of various antioxidant enzymes, including superoxide dismutase (SOD) and catalase, rather than just glutathione [1]. In the ovary, ROS-induced oxidative stress causes damage to ovarian follicles caused by toxins that are currently being studied using models induced by exposure to various chemicals (eg, cyclophosphamide, 4 -vinyl cyclohexene epoxide, ionizing radiation, and H. pylori).
). ROS are also produced by normal intracellular metabolic processes; However, if the ROS produced are not removed in time, their accumulation causes oxidative stress, which disturbs the homeostasis of oxidation and reduction processes [2]. Depending on these ROS levels, meiotic cell cycle progression and cell death can affect oocyte physiology [3, 4]. Additionally, ROS levels are associated with fertility rates and reproductive outcomes. According to previous reports, moderate levels of ROS promote M-II arrest as well as resumption of oocyte meiosis from diplotene. However, high levels of ROS cause cell death (eg, apoptosis and necrosis) and lead to meiotic cell cycle arrest [5, 6]. Granulosa cells are very sensitive to ROS, which can cause granulosa cell death. In the follicular tissue, macrophages can produce high levels of ROS; This can lead to the death of the oocyte cell as well as the surrounding granulosa cells because ROS can pass through the cell membrane and affect the surrounding cells. These findings indicate that ROS and the level of ROS regulation play an important role in ovarian function.
Mesenchymal stem cells (MSCs) have been identified in the fields of sepsis, degenerative diseases, autoimmune diseases, and transplantation therapy due to their beneficial properties such as self-renewal, multilineage differentiation, immune modulation, and cytokine and growth factor secretion. In addition, the mode of action (MOA) of ROS has been shown to produce multiple, antiapoptotic, anti-inflammatory, and antioxidant effects [7]. Recently, among MSCs, human platelet-derived MSCs (PD-MSCs) have been reported to have the ability to treat various degenerative diseases (eg, liver cirrhosis, chemically and surgically induced ovarian dysfunction, and skin lesions ) [8]. , 9, 10]. This ability is due to the fact that these cells have beneficial therapeutic effects, such as the lack of immune rejection and ethical issues compared to other types of MSCs. In particular, the antiapoptotic effect of MSCs is the mechanism underlying the recovery of organ functions in several diseases. Many researchers have suggested that the paracrine effect of MSCs through the production of various cytokines is a powerful mechanism that has a therapeutic effect [11]. Previous reports have shown that PD-MSC can restore ovarian function, including reproductive hormone production and follicle development, by promoting proliferation, vascular remodeling, and antioxidant effects [9, 12 , 13].
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To support the development of stem cell therapy based on these findings, more than 500 clinical trials have been registered at ClinicalTrials (www.clinicaltrials.gov; accessed January 10, 2023), aiming to study the effect stem cells in almost all clinical applications. . neurodegenerative and cardiac disorders, graft-versus-host disease, perianal fistula, etc. including treatment. www.clinicaltrials.gov). Although many clinical trials have been registered on the use of stem cell therapy to treat premature ovarian failure (POF), these studies have many limitations due to the lack of clear preclinical results and the progress of clinical trials [ 14]. The reason for poor treatment development is the lack of clear recommendations for treatment development, specific standardization based on the effective MOA, the number of cells required, and the optimal injection route. In one of the reported preclinical studies, Wang and colleagues investigated the effect of UC-MSC transplantation at a density of 0.25 × 10 cells.
Cells/mL via tail vein in autoimmune-induced POF mice. The authors reported that the effect of umbilical cord mesenchymal stem cell (UC-MSC) transplantation increases with increasing cell dose (15). However, the paucity of studies on the relationship between cell dose and therapeutic effect makes the results inconclusive; Therefore, studies on stem cell dosage and type in different models of ovarian dysfunction are needed. On this basis, although several studies have been carried out on the effectiveness of different concentrations of stem cells in models of ovarian disorders, including degenerative diseases, it is important and necessary to determining the correct stem cell concentration to achieve therapeutic efficacy. cell therapies. [16, 17].
Although we have reported the therapeutic effect of PD-MSCs in mice with ovarian failure, there is still a lack of evidence regarding the optimal cell dose for the development of stem cell therapy for ovarian failure disease. . Therefore, the purpose of this study was to compare the efficacy of transplantation of three different concentrations of cells in mice with ovarian dysfunction as a result of a surgical procedure other than ovariectomy and to determine whether ovarian function was development through key MOAs such as antioxidant effects. .
With approval from the Institutional Review Board (IRB) of CHA General Hospital (IRB07-18; Seoul, Korea), human PD-MSCs were isolated from the chorionic plate membrane of placental tissue, the fetal side of the placenta. collected at term (38 ± 2 weeks gestation) after obtaining patient consent for use
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