Extracellular vesicles from iPSC-MSCs alleviate chemotherapy-induced mouse ovarian damage via the ILK-PI3K/AKT pathway

Cao, Ruican; Lv, Yao; Lü, Gang; Liu, Hongbin; Wang, WuMing; Tan, ChunLai; Su, Xianwei; Xiong, ZhiQiang; Ma, Jinlong; Chan, Wai‐Yee

doi:10.24272/j.issn.2095-8137.2022.340

Cited by 10 publications

(7 citation statements)

References 57 publications

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“…Furthermore, it was confirmed by a series of experiments, including a non-contact co-culture system and the addition of inhibitors (chiauranib, 3-methyladenine, and rapamycin) in vitro. The results were consistent with existing studies [ 49 , 59 ]. Although chiauranib is a multi-target inhibitor against aurora B kinase, VEGFR, colony-stimulating factor 1 receptor, platelet-derived growth factor receptor in tumor angiogenesis [ 60 ], the results of MSCs and VEGFA co-culture with KGN and GCs revealed that chiauranib targeted VEGFR2 on the cell membrane, and suggested that paracrine VEGFA of hUC-MSCs mitigated the CTX-induced excessive autophagy.…”

Section: Discussionsupporting

confidence: 93%

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model

Dai,

Yang,

et al. 2023

J Ovarian Res

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Background Premature ovarian failure (POF) is one of the leading causes of female infertility and is accompanied by abnormal endocrine, seriously affecting female quality of life. Previous studies have demonstrated that mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for POF. However, the mechanism remains obscure. This study aims to investigate the therapeutic effect of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on ovarian function in the POF rat model and explore the underlying mechanisms. Methods The ovarian function was evaluated by ovarian morphology, histology, estrous cycle, hormone levels (AMH, E2, FSH, and LH), and fertility ability to investigate the effect of hUC-MSCs on the POF rats model. The cytokines levels were assayed in serum using protein array to explore the mechanisms of hUC-MSCs therapy for POF. The excessive autophagy levels were evaluated using a co-culture system of 3D MSCs spheroids with human ovarian granulosa cell line (KGN) or primary ovarian granulosa cells (GCs) to understand the paracrine effect of hUC-MSCs on GCs. The related proteins expression of autophagy and PI3K/AKT/mTOR pathway was detected using Western Blotting and/or in various inhibitors supplement to further demonstrate that vascular endothelial growth factor A (VEGFA) secreted by hUC-MSCs can alleviate excessive autophagy of ovarian GCs via PI3K/AKT/mTOR signaling pathway. The ovarian culture model in vitro was applied to confirm the mechanism. Results The ovarian function of POF and the excessive autophagy of ovarian GCs were restored after hUC-MSCs transplantation. The protein array result demonstrated that VEGF and PI3K/AKT might improve ovarian function. in vitro experiments demonstrated that VEGFA secreted by hUC-MSCs could decrease oxidative stress and inhibit excessive autophagy of ovarian GCs via PI3K/AKT/mTOR pathway. The ovarian culture model results confirmed this mechanism in vitro. Conclusion The hUC-MSCs can alleviate excessive autophagy of ovarian GCs via paracrine VEGFA and regulate the PI3K/AKT/mTOR signaling pathway, thereby improving the ovarian function of POF.

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Section: Discussionsupporting

confidence: 93%

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model

Dai,

Yang,

et al. 2023

J Ovarian Res

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“…Also, it was demonstrate that OGLCs derived from iPSCs can repair damaged ovarian tissue and promote follicular development in a mouse model of POI [ 93 ]. Therapeutic effect of iPSC-MSC-EVs can bemediated through up-regulation of the integrin-linked kinase (ILK) -PI3K/AKT pathway in GC, a key mediator in cell proliferation and survival [ 222 ]. Despite of attractive results, there are several limitation in regard to ovarian somatic cells extraction and low efficacy of the iPS differentiation into mature oocytes [ 223 ].…”

Section: Optimizing Mscs For Therapeutic Purposesmentioning

confidence: 99%

Protective role of stem cells in POI: Current status and mechanism of action, a review article

Sadeghi,

Mosaffa,

Huang

et al. 2024

Heliyon

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“…MSCs-derived EVs carry substances such as nucleic acids, proteins, lipids, and metabolites from parental cells, and their therapeutic potential for POI has now been demonstrated. Relevant basic studies in recent years have shown that MSCs and their derived EVs have similar therapeutic effects on POI [ 24 – 45 ] (Tables 1 , 2 ).…”

Section: Comparison Of the Therapeutic Effects Of Mscs And Mscs-deriv...mentioning

confidence: 99%

“…Relevant basic studies in recent years have shown that MSCs and their derived EVs have similar therapeutic effects on POI [ 24 – 45 ] (Tables 1 , 2 ).…”

Section: Comparison Of the Therapeutic Effects Of Mscs And Mscs-deriv...mentioning

confidence: 99%

The remodeling of ovarian function: targeted delivery strategies for mesenchymal stem cells and their derived extracellular vesicles

Song,

Wu,

Liu

et al. 2024

Stem Cell Res Ther

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Premature ovarian insufficiency (POI) is an essential cause of reduced fertility and quality of life in young women. Mesenchymal stem cells (MSCs) and MSCs-derived extracellular vesicles (EVs) have the ability to migrate to damaged tissues and are considered as promising therapeutic approaches for POI. However, the homing ability and therapeutic efficacy of MSCs administered in vivo are still insufficient, and their potential tumorigenicity and multi-differentiation potential also bring many doubts about their safety. The targeting ability and migration efficiency of MSCs can be improved by genetic engineering and surface modification, thereby maximizing their therapeutic efficacy. However, the use of viral vectors also has increased safety concerns. In addition, EVs, which seem to be the current therapeutic alternative to MSCs, are still poorly targeted for distribution, although they have improved in terms of safety. This paper reviews the comparative therapeutic effects of MSCs and their derived EVs on POI, their biodistribution after in vivo administration, and the most important possible ovarian targeting strategies. Difficulties such as homogeneity and yield before clinical application are also discussed. This article will provide new insights into precision therapy and targeted drug delivery for female ovarian diseases. Graphical Abstract

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Extracellular vesicles from iPSC-MSCs alleviate chemotherapy-induced mouse ovarian damage via the ILK-PI3K/AKT pathway

Cited by 10 publications

References 57 publications

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) alleviate excessive autophagy of ovarian granular cells through VEGFA/PI3K/AKT/mTOR pathway in premature ovarian failure rat model

Protective role of stem cells in POI: Current status and mechanism of action, a review article

The remodeling of ovarian function: targeted delivery strategies for mesenchymal stem cells and their derived extracellular vesicles

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