A comparative study of Mesenchymal Stem Cells transplantation approach to antagonize age-associated ovarian hypofunction with consideration of safety and efficiency,Journal of Advanced Research

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A comparative study of Mesenchymal Stem Cells transplantation approach to antagonize age-associated ovarian hypofunction with consideration of safety and efficiency
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2021-09-06 , DOI: 10.1016/j.jare.2021.09.001
Lingjuan Wang ₁ , Qiaojuan Mei ₂ , Qin Xie ₁ , Huiying Li ₂ , Ping Su ₂ , Ling Zhang ₂ , Kezhen Li ₁ , Ding Ma ₁ , Gang Chen ₁ , Jing Li ₃ , Wenpei Xiang ₂

Affiliation

Introduction

The transplantation of mesenchymal stem cells (MSCs) in patients with premature ovarian failure (POF) could lead to clinical improvement. The transplantation to the ovaries among other transplantation methods have been reported in various animal models, however, there is little evidence regarding the optimal method, including the clinical safety and the efficiency for the treatment of age associated ovarian hypofunction.

Objectives

To establish the most effective transplantation route of MSCs, explore the resistance to therapy, its safety and role in the natural aging process of the ovaries.

Methods

Highly purified MSCs were injected intraperitoneally, directly into the ovaries or tail-intravenously in mice animal model. The ovarian function, quantity and quality of oocytes, cell viability/apoptosis, were evaluated, applying chemiluminescence analysis (CLIA), western blotting, immunofluorescence staining, transmission electron microscope (TEM), TdT mediated dUTP Nick End Labeling (TUNEL) assay and other techniques. The organ tumorigenicity was also evaluated by long-term observation and histopathological examination. The efficiency of MSCs was further verified in non-human primates by the most effective transplantation route.

Results

The 32nd week was ultimately determined as the time point of MSCs transplantation. Our results showed that the intra-ovarian injection was the best transplantation method with a more conspicuous effect. With deeper investigations, we found that the transplanted MSCs showed an effective influence on the follicular number, promoted follicle maturation and inhibited cell apoptosis, which was further verified in non-human primates. In addition, the long-term observation and the histopathological examinations ruled out neoplasms or obvious prosoplasia after MSCs transplantation.

Conclusion

MSCs transplantation by intra-ovarian injection could within a month exert the most conspicuous anti-age-associated ovarian hypofunction effects, which may improve the quantity and quality of oocytes by changing the mitochondrial structure, regulating mitochondrial function and attenuating cell apoptosis to increase the storage of the follicle pool without a remarkable potential of tumorigenicity.

中文翻译：

考虑安全性和有效性的间充质干细胞移植方法对抗年龄相关性卵巢功能减退的比较研究

介绍

在卵巢早衰（POF）患者中移植间充质干细胞（MSCs）可能会导致临床改善。在各种动物模型中已经报道了移植到卵巢以及其他移植方法，然而，关于最佳方法的证据很少，包括临床安全性和治疗年龄相关性卵巢功能减退的效率。

目标

为建立最有效的间充质干细胞移植途径，探讨其对治疗的抵抗力、安全性以及在卵巢自然衰老过程中的作用。

方法

在小鼠动物模型中，将高度纯化的 MSCs 腹膜内、直接注射到卵巢或尾部静脉注射。采用化学发光分析（CLIA）、蛋白质印迹、免疫荧光染色、透射电子显微镜（TEM）、TdT介导的dUTP缺口末端标记（TUNEL）测定等方法评估卵巢功能、卵母细胞数量和质量、细胞活力/凋亡技巧。还通过长期观察和组织病理学检查评估器官致瘤性。通过最有效的移植途径，在非人灵长类动物中进一步验证了 MSCs 的效率。