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Chen L, Wu Y, Lv T, Tuo R, Xiao Y. Mesenchymal stem cells enchanced by salidroside to inhibit ferroptosis and improve premature ovarian insufficiency via Keap1/Nrf2/GPX4 signaling. Redox Rep 2025; 30:2455914. [PMID: 39874130 PMCID: PMC11776066 DOI: 10.1080/13510002.2025.2455914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Regenerative medicine researches have shown that mesenchymal stem cells (MSCs) may be an effective treatment method for premature ovarian insufficiency (POI). However, the efficacy of MSCs is still limited. PURPOSE This study aims to explain whether salidroside and MSCs combination is a therapeutic strategy to POI and to explore salidroside-enhanced MSCs inhibiting ferroptosis via Keap1/Nrf2/GPX4 signaling. METHODS The effect of salidroside and MSCs on ovarian granular cells (GCs) was analyzed. After treatment, hormone levels and -fertility of rats were measured. Lipid peroxidation levels, iron deposition and mitochondrial morphology were detected. The genes and proteins of Keap1/Nrf2/GPX4 signaling were examined. RESULTS Salidroside and MSCs were found to inhibit cell death of GCs by reducing peroxidation and intracellular ferrous. Salidroside promotes the proliferation of MSCs and supports cell survival in ovary. Salidroside combined with MSCs therapy restored ovarian function, which was better than MSCs monotherapy. Salidroside-enhanced MSCs to inhibit ferroptosis. The results showed activation of the Keap1/Nrf2/GPX4 signaling and an increase in anti-ferroptosis molecule. CONCLUSIONS Salidroside-enhanced MSCs as a ferroptosis inhibitor and provide new therapeutic strategies for POI. The possible mechanisms of MSCs were related to maintaining redox homeostasis via a Keap1/Nrf2/GPX4 signaling.
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Affiliation(s)
- Lixuan Chen
- Department of Hematology, Shenzhen Qianhai Shekou Pilot Free Trade Zone Hospital, Shenzhen, People’s Republic of China
| | - Yingnan Wu
- Translational Medicine Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China
| | - Tiying Lv
- Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Rui Tuo
- Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Yang Xiao
- Department of Hematology, Shenzhen Qianhai Shekou Pilot Free Trade Zone Hospital, Shenzhen, People’s Republic of China
- Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
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Keikha F, Moghadam FR, Shoarishoar SS, Tarafdari A, Ghaemi M. The efficacy of intraovarian versus subcutaneous corifollitropin alfa administration in DuoStim protocol for infertile women with low in vitro fertilization response. J Obstet Gynaecol Res 2025; 51:e16316. [PMID: 40369953 DOI: 10.1111/jog.16316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 04/28/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND AND AIM Infertility in women, particularly those with a poor response to in vitro fertilization (IVF), poses significant challenges in reproductive medicine. This study aimed to compare the effectiveness of intraovarian versus subcutaneous injection of corifollitropin alfa in the DuoStim protocol among infertile women exhibiting a poor response to IVF, with a specific focus on oocyte retrieval counts and quality. MATERIALS AND METHODS A total of 40 poorly responding infertile women were randomly assigned to two groups: 20 women received corifollitropin alfa via intraovarian injection, and 20 women received it via subcutaneous injection. Key demographic data, cycle duration, gonadotropin dosage, the number of oocytes retrieved, and oocyte quality (specifically Grade B oocytes) were assessed. RESULTS Demographic analyses revealed no significant differences between the two groups in terms of age (subcutaneous: 37.91 ± 6.11 years; intraovarian: 36.84 ± 5.42 years; p = 0.17) or weight (subcutaneous: 74.15 ± 10.51 kg; intraovarian: 78.24 ± 13.22 kg; p = 0.42). The number of oocytes retrieved during both phases did not significantly differ, but the intraovarian group yielded a notably higher number of Grade B oocytes during the follicular phase (p = 0.02). No significant differences were observed in cycle duration (p > 0.05) or the final dose of gonadotropins administered (p > 0.05). CONCLUSION The study revealed that intraovarian injection of corifollitropin alfa may enhance the quality of oocytes retrieved, particularly Grade B oocytes, in women with poor response to IVF under the DuoStim protocol, while both methods exhibited similar outcomes in terms of demographic factors, cycle duration, and gonadotropin dosage.
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Affiliation(s)
- Fatemeh Keikha
- Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Firoozeh Rakhshani Moghadam
- Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyedeh Shahed Shoarishoar
- Reproductive Health Research Center, Department of Obstetrics and Gynecology, Al-zahra Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Azadeh Tarafdari
- Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Marjan Ghaemi
- Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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Zhang Y, Liu H, Lou Y, Li J, Liu C, Zhang H, Zhang C, Guo Q, Liu X, Yang W, Li J, Tian T, Zeng L, Xu H, Yang S, Zhen X, Bi H, Yang R, Yu Y, Ma C, Li R, Liu P, Qiao J. Efficacy and safety of autologous adipose tissue-derived stromal vascular fraction in patients with premature ovarian insufficiency: protocol for a single-centre randomised controlled trial. BMJ Open 2025; 15:e093804. [PMID: 40180397 PMCID: PMC11969603 DOI: 10.1136/bmjopen-2024-093804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 03/25/2025] [Indexed: 04/05/2025] Open
Abstract
INTRODUCTION Premature ovarian insufficiency (POI) is a complicated reproductive endocrine disease seriously affecting physiological function and fertility in women. Its clinical features include amenorrhoea or infrequent menstruation, oestrogen deficiency and elevated levels of gonadotropins. At present, conventional treatments for POI in clinical practice are unable to fundamentally improve ovarian function or solve fertility problems, and often have certain side effects. Adipose tissue-derived stromal vascular fraction (SVF) contains various cell types, including adipose-derived stem/stromal cells, stromal cells, endothelial cells, fibroblasts and macrophages. Recently, SVF has shown tremendous potential in treating many refractory diseases, offering a promising therapeutic option for improving ovarian function. Although SVF has shown therapeutic effects in animal models of POI, there is insufficient evidence demonstrating the efficacy and safety of autologous SVF in women with POI. METHODS AND ANALYSIS This study is a single-centre randomised controlled trial designed to explore the efficacy and safety of using autologous SVF in improving pregnancy outcomes in patients with infertility diagnosed with POI. A total of 308 women meeting the eligibility criteria will be randomly assigned in a 1:1 ratio to either the SVF group or the control group. The control group will receive conventional assisted reproductive technology treatment, including in vitro fertilisation, embryo transfer and intracytoplasmic sperm injection. In the SVF group, patients will undergo bilateral intraovarian injections of the SVF suspension under ultrasound guidance. Their in vitro fertilisation cycles will commence 4-8 weeks after SVF injection. The primary outcome of this trial is the cumulative clinical pregnancy rate within 6 months. Aside from this, secondary outcomes including menstrual volume and duration, ovarian volume, antral follicle count, and serum levels of anti-mullerian hormone and sex hormone (oestrogen and follicle-stimulating hormone) will be measured. All adverse events will be monitored and recorded within a 6-month follow-up period. Additionally, pregnancy outcomes and the health status of the offspring will be tracked through telephone follow-up for 2 years. ETHICS AND DISSEMINATION This trial has been reviewed and approved by the Ethics Committee of Peking University Third Hospital (approval number: IRB00006761-M2024330). We will ensure that each patient has signed informed consent before participation in the trial. The findings will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER NCT06481969.
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Affiliation(s)
- Yaodong Zhang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Hui Liu
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
- Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Yanru Lou
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Jialin Li
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Chenhong Liu
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Hongxia Zhang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Chen Zhang
- Department of Plastic Surgery, Peking University Third Hospital, Beijing, China
| | - Qing Guo
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
- Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Xiaojuan Liu
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
- Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Wan Yang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Jia Li
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Tian Tian
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Lin Zeng
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
| | - Huiyu Xu
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Shuo Yang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Xiumei Zhen
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Hongsen Bi
- Department of Plastic Surgery, Peking University Third Hospital, Beijing, China
| | - Rui Yang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Yang Yu
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
- Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Caihong Ma
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Rong Li
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Ping Liu
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Jie Qiao
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
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Soleimany Z, Siadat F, Farhadi M, Mirshaby ZS, Sanadgol Z, Eyni H. Improvement of ovarian function in a premature ovarian failure mouse model using Vitex agnus-castus extract. JBRA Assist Reprod 2025; 29:117-126. [PMID: 39835794 PMCID: PMC11867258 DOI: 10.5935/1518-0557.20240101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 12/26/2024] [Indexed: 01/22/2025] Open
Abstract
OBJECTIVE Premature ovarian failure (POF) leads to infertility. Numerous researchers have endeavored to enhance ovarian function through antioxidant interventions. Extract from Vitex agnus-castus (VAC) has demonstrated a protective effect. Therefore, the objective of this study was to investigate the amelioration of ovarian function following VAC treatment in a POF mouse model. METHODS In this investigation, 30 female NMRI mice were categorized into control, POF model (cyclophosphamide 120 mg/kg I.P), and experimental groups (100, 300, and 500 of VAC extract). Parameters such as body weight, vaginal smears, and follicular evaluation were examined. FSH, estradiol levels, free radicals, and the expression of the FMR1 gene were assessed. RESULTS The microscopic assessment revealed that POF induced morphological alterations in ovarian tissue, whereas VAC treatment significantly ameliorated ovarian tissue conditions. The follicles number exhibited a significant reduction in the POF group; however, VAC led to an increase in follicular count and elevated estradiol levels in the treatment groups. Serum FSH levels displayed an elevation in the POF group, whereas the treatment groups exhibited a substantial reduction in FSH levels compared to the POF group. The expression of the FMR1 gene demonstrated upregulation in the POF group compared to the control group (p<0.05). Moreover, this expression significantly decreased in the 500-dose VAC group compared to the POF group (p<0.001). ROS generation exhibited a significant increase in the POF group, which was conversely mitigated in all experimental groups. CONCLUSIONS Our findings underscore the potential of this extract to ameliorate POF symptoms, however, further investigations are needed.
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Affiliation(s)
- Zeinab Soleimany
- Department of Biology, North Tehran Branch, Islamic Azad
University, Tehran, Iran
| | - Fatemeh Siadat
- Department of Biology, North Tehran Branch, Islamic Azad
University, Tehran, Iran
| | - Mona Farhadi
- Department of Microbiology, Karaj Branch, Islamic Azad University,
Karaj, Iran
| | | | - Zahra Sanadgol
- Department of Microbiology, Karaj Branch, Islamic Azad University,
Karaj, Iran
| | - Hossein Eyni
- Stem Cell and Regenerative Medicine Research Center, Department of
Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Zhao X, Yu Z, Wang X, Li X, Liu Y, Wang L. The administration of human amniotic epithelial cells in premature ovarian insufficiency: From preclinical to clinical. Gynecol Endocrinol 2024; 40:2382818. [PMID: 39039858 DOI: 10.1080/09513590.2024.2382818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 07/12/2024] [Indexed: 07/24/2024] Open
Abstract
Premature ovarian insufficiency (POI) or premature ovarian failure (POF) is a multifactorial disorder occurring in reproductive-age women, characterized by elevated levels of follicle-stimulating hormone (FSH) and irregular or absent menstrual cycles, often accompanied by perimenopausal symptoms and infertility. While assisted reproductive technology can address the reproductive aspirations of some POI-affected women, it is hindered by issues such as exorbitant expenses, substantial risks, and poor rates of conception. Encouragingly, extensive research is exploring novel approaches to enhance fertility, particularly in the realm of stem cell therapy, showcasing both feasibility and significant potential. Human amniotic epithelial cells (hAECs) from discarded placental tissues are crucial in regenerative medicine for their pluripotency, low immunogenicity, non-tumorigenicity, accessibility, and minimal ethical concerns. Preclinical studies highlight the underlying mechanisms and therapeutic effects of hAECs in POI treatment, and current research is focusing on innovative interventions to augment hAECs' efficacy. However, despite these strides, overcoming application challenges is essential for successful clinical translation. This paper conducted a comprehensive analysis of the aforementioned issues, examining the prospects and challenges of hAECs in POI, with the aim of providing some insights for future research and clinical practice.
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Affiliation(s)
- Xiaojing Zhao
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhongna Yu
- Department of Gynecology, The Affiliated People's Hospital, Ningbo University, Ningbo, Zhejiang, China
| | - Xinrun Wang
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiaojing Li
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yang Liu
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Liang Wang
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Yuan Z, Zhang Y, He X, Wang X, Wang X, Ren S, Su J, Shen J, Li X, Xiao Z. Engineering mesenchymal stem cells for premature ovarian failure: overcoming challenges and innovating therapeutic strategies. Theranostics 2024; 14:6487-6515. [PMID: 39479455 PMCID: PMC11519806 DOI: 10.7150/thno.102641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 09/23/2024] [Indexed: 11/02/2024] Open
Abstract
Premature ovarian failure (POF) is a leading cause of infertility in women, causing significant psychological and physical distress. Current therapeutic options are limited, necessitating the exploration of new treatments. Mesenchymal stem cells (MSCs), known for their remarkable homing and regenerative properties, have emerged as a promising intervention for POF. However, their clinical efficacy has been inconsistent. This paper aims to address these challenges by examining the cellular heterogeneity within MSC populations, which is crucial for identifying and selecting specific functional subpopulations for clinical applications. Understanding this heterogeneity can enhance therapeutic efficacy and ensure treatment stability. Additionally, this review comprehensively examines the literature on the effectiveness, safety, and ethical considerations of MSCs for ovarian regeneration, with a focus on preclinical and clinical trials. We also discuss potential strategies involving genetically and tissue-engineered MSCs. By integrating insights from these studies, we propose new directions for the design of targeted MSC treatments for POF and related disorders, potentially improving outcomes, addressing safety concerns, and expanding therapeutic options while ensuring ethical compliance.
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Affiliation(s)
- Zijun Yuan
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yinping Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xinyu He
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xingyue Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Siqi Ren
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jiahong Su
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
| | - Xiang Li
- Sichuan College of Traditional Chinese Medicine, Sichuan Mianyang 621000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Department of Pharmacology, School of Pharmacy, Sichuan College of Traditional Chinese Medicine, Sichuan Mianyang 621000, China
- Luzhou People's Hospital, Luzhou, Sichuan, China
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Weng L, Wei L, Zhang Q, Sun T, Kuang X, Huang Q, Cao Y, Liu X, Wang Q, Guo Y, Sun J, Wang L, Tang H, Yang H, Chen Q, Zhang J, Wang B, Qian Z, Lai D. Safety and efficacy of allogenic human amniotic epithelial cells transplantation via ovarian artery in patients with premature ovarian failure: a single-arm, phase 1 clinical trial. EClinicalMedicine 2024; 74:102744. [PMID: 39165278 PMCID: PMC11334649 DOI: 10.1016/j.eclinm.2024.102744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 06/25/2024] [Accepted: 07/05/2024] [Indexed: 08/22/2024] Open
Abstract
Background Premature ovarian failure (POF) is a prevalent and severe condition that impairs female health but there is currently no effective treatment available to restore ovarian function. Human amniotic epithelial cells (hAECs) exhibit ovarian protection in pre-clinical models. Thus, we conducted a single-arm, phase 1 clinical trial to assess the safety and efficacy of allogenic hAECs in treating POF. Methods A total of 35 patients received 6 × 107 hAECs via ovarian artery and completed a five-month follow-up from December 30, 2020 to January 31, 2022. The follow-up assessments were conducted at various intervals after hAECs treatment, including one month (Visit-1, V-1), three months (Visit-2, V-2), and five months (Visit-3, V-3) post-treatment. The primary endpoints were incidence of adverse events (AEs), and clinically significant laboratory abnormalities. Secondary endpoints included evaluation of transvaginal ultrasound results, sex hormone levels, Menopausal Quality of Life (MENQOL) questionnaire, as well as reproductive indicators. This trial was registered at www.clinicaltrials.gov as NCT02912104. Findings No serious AEs were observed throughout the five-month follow-up period. The most common AE was hematoma (7/35, 20.00%), and other AEs include pelvic pain (4/35, 11.43%), fever (2/35, 5.71%), anaphylaxis (2/35, 5.71%), and hepatotoxicity (1/35, 2.86%). After hAECs transplantation (hAECT), significant improvements were observed in the levels of endometrial thickness, left ovarian volume, sex hormones (follicle-stimulating hormone (FSH) and estradiol (E2)), and MENQOL scores in all patients during the five-month follow-up period. Among them, 13 participants (37.14%) experienced spontaneous menstrual bleeding, and 20.00% (7/35) reported more than one regular menstrual bleeding post-hAECT. In this response group, significant improvements were observed in endometrial thickness, left ovarian volume, levels of FSH, E2, anti-Müllerian hormone (AMH), and MENQOL scores one month after hAECT in comparison to pre-hAECT. Interpretation hAECT via ovarian artery is safe, well-tolerated and temporarily ameliorates endometrial thickness, ovarian size, hormone levels, and menopausal symptoms in POF patients. Further randomized controlled trial of hAECs with longer follow-up period and a larger sample size is warranted. Funding National Natural Science Foundation of China (No. 82271664), the Interdisciplinary Program of Shanghai Jiao Tong University (YG2022ZD028), the Shanghai Municipal Health Committee (202240345), Shanghai Key Laboratory of Embryo Original Diseases (No. Shelab2022ZD01), Shanghai Municipal Education Commission (No. 20152236), and National Key Research and Development Program of China (No. 2018YFC1004802), Shanghai Clinical Research Center for Cell Therapy, China (No. 23J41900100).
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Affiliation(s)
- Lichun Weng
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Liutong Wei
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Qiuwan Zhang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Taotao Sun
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Xiaojun Kuang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Qin Huang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Yunyun Cao
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Xiaoyi Liu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Qian Wang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Ying Guo
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Junyan Sun
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Lulu Wang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Haihong Tang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Haiou Yang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Qian Chen
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Jian Zhang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Bingshun Wang
- The International Peace Maternity and Child Health Hospital, Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Zhaoxia Qian
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Dongmei Lai
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
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Hu L, Tan R, He Y, Wang H, Pu D, Wu J. Stem cell therapy for premature ovarian insufficiency: a systematic review and meta-analysis of animal and clinical studies. Arch Gynecol Obstet 2024; 309:457-467. [PMID: 37264272 DOI: 10.1007/s00404-023-07062-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 04/28/2023] [Indexed: 06/03/2023]
Abstract
PURPOSE The aim of this systematic review and meta-analysis is to evaluate the efficacy of stem cell therapy in mouse models of POI and patients with POI. METHODS The PubMed, Web of Science, and Embase databases were searched from inception to February 2022 for relevant animal and clinical studies. The reference lists of the included reviews were manually searched to identify additional eligible studies. Data were independently extracted by two investigators, and disagreements were resolved by discussion. SYRCLE's risk of bias tool and the MINORS tool were used to assess the quality of animal and clinical studies by two independent investigators. All statistical analyses were conducted using Review Manager 5.3 software. RESULTS A total of twenty animal studies and six clinical studies were included in this meta-analysis. In animal studies, the results showed that stem cells could improve hormone levels, follicle count, estrous cycle and pregnancy outcome. For hormone levels, stem cells increased serum E2 and AMH levels and decreased serum FSH and LH levels compared with the control group (serum E2 level: SMD: 5.05, 95% CI 4.21-5.90, P < 0.00001; serum AMH level: SMD: 4.42, 95% CI 3.06-5.79, P < 0.00001; serum FSH level: SMD: - 3.79, 95% CI - 4.87 to - 2.70, P < 0.00001; serum LH level: SMD: - 1.31, 95% CI - 1.65 to - 0.96, P < 0.00001). All follicle counts, except for the antral follicle count, were significantly changed compared with the control group. (primordial follicle count: SMD: 4.61, 95% CI 3.65-5.56, P < 0.00001; primary follicle count: SMD: 3.35, 95% CI 1.08-5.63, P = 0.004; secondary follicle count: SMD: 3.23, 95% CI 1.92-4.55, P < 0.00001; total follicle count: SMD: 4.84, 95% CI 2.86-6.83, P < 0.00001; oocyte count: SMD: 7.56, 95% CI 5.92-9.20, P < 0.00001; atretic follicle count: SMD: - 1.79, 95% CI - 2.59 to - 1.00, P < 0.00001). For the estrous cycle, stem cell therapy increased the number of estrous cycles (WMD: 2.72, 95% CI 2.07-3.37, P < 0.00001) and decreased the duration of the estrous cycle (WMD: - 1.26, 95% CI - 1.84 to - 0.69, P < 0.0001) compared with the control group. For pregnancy outcomes, stem cell therapy increased the fertility rate (RR: 3.00, 95% CI 1.74-5.17, P < 0.0001) and litter size (WMD: 3.82, 95% CI 0.36-7.28, P = 0.03) compared with the control group. In animal studies, the asymmetric funnel plot of serum E2 and FSH levels indicated the possibility of publication bias. Unpublished and negative studies may be the source of publication bias. In clinical studies, the results showed that stem cell therapy could decrease serum FSH level (MD: - 30.32, 95% CI - 59.03 to - 1.01, P = 0.04) and increase AFC (MD: 1.07, 95% CI 0.70-1.43, P < 0.00001), pregnancy rate (RD: 0.19, 95% CI 0.04-0.34, P = 0.01) and live birth rate (RD: 0.19, 95% CI 0.07-0.31, P = 0.001) in POI patients. In addition, there was no significant difference in menstrual function regained (RD: 0.22, 95% CI - 0.03-0.46, P = 0.09), oocytes retrieved (MD: 1.00, 95% CI - 0.64-2.64, P = 0.23) and embryos (MD: 0.80, 95% CI - 0.15-1.76, P = 0.10) between different groups. CONCLUSION This meta-analysis suggested that stem cell therapy might be effective in POI mouse models and patients and could be considered a potential treatment to restore fertility capability in POI patients.
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Affiliation(s)
- Luanqian Hu
- Department of Obstetrics and Gynecology, Jiangsu Province Hospital, Jiangsu Women and Children Health Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rongrong Tan
- Department of Obstetrics and Gynecology, Jiangsu Province Hospital, Jiangsu Women and Children Health Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuheng He
- Department of Obstetrics and Gynecology, Jiangsu Province Hospital, Jiangsu Women and Children Health Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huiyuan Wang
- Department of Obstetrics and Gynecology, Jiangsu Province Hospital, Jiangsu Women and Children Health Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Danhua Pu
- Department of Obstetrics and Gynecology, Jiangsu Province Hospital, Jiangsu Women and Children Health Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Jie Wu
- Department of Obstetrics and Gynecology, Jiangsu Province Hospital, Jiangsu Women and Children Health Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Wang Y, Mou Q, Yi H, Meng Z. Transient Fever: The Sole Treatment-Related Adverse Event Associated with Mesenchymal Stromal Cells and Solid Clues from the Real World. Curr Stem Cell Res Ther 2024; 19:1263-1285. [PMID: 37909436 DOI: 10.2174/011574888x179799231023060734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/12/2023] [Accepted: 08/24/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND The number of trials investigating mesenchymal stromal cells (MSCs) soars within 3 years which urges a study analysing emerging MSC treatment-related adverse events. AIM To assess the safety of MSC therapy and provide solid evidence for clinical translation of MSC. METHODS A meta-analysis of randomized clinical trials (RCTs) published up to April 20th, 2023 was performed. Odds ratio (OR) and 95% confidential intervals (CIs) were used to display pooled results. RESULTS 152 randomized clinical trials (RCTs) that incorporated 9228 individuals treated with MSCs from autologous or allogenic adipose tissue, bone marrow, Wharton's Jelly, and placenta tissue were included in the analysis. We discovered appropriate 21 MSC treatment-related adverse events (TRAEs), of which fever [OR, 1.61, 95% CI: 1.22-2.11, p<0.01] was the sole event that was closely associated with MSC therapy. MSCs also trended to lower the incidence rate of tachycardia [OR, 0.83, 95% CI: 0.64-1.09, p=0.14] and fatigue [OR, 0.18, 95% CI: 0.61-1.07, p=0.18]. A separate analysis of studies with long-term follow-up (more than 1 year) demonstrated the close relationship between MSCs and fever [OR, 1.75, 95% CI: 1.26-2.24, p<0.01]. The rest TRAEs did not associate themselves with MSC therapy. Dose-response was also conducted for fever, linearity was discovered between MSCs from allogeneic tissue and Wharton's Jelly and fever. CONCLUSION To date, our results suggest that fever is the only AE closely associated with MSCs.
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Affiliation(s)
- Yang Wang
- Department of Orthopedics, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Number, 250, Changgang East Road, Haizhu District, Guangzhou, Guangdong Province, China
| | - Qiuying Mou
- Clinical Medicine College, Guangdong Pharmaceutical University, Number, 280, Waihuan East Road, Guangzhou Higher Education Mega Center, Guangzhou, Guangdong Province, China
| | - Hanxiao Yi
- Department of Radiotherapy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Number, 600, Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Zilu Meng
- Department of Maxillofacial Surgery, The First Affiliated Hospital of Guangdong Pharmaceutical University, China
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Jia L, Wang W, Liang J, Niu S, Wang Y, Yang J, Li L, Wang G, Xu X, Mu L, Cheng K, Yang X, Wang Y, Luo H, Xia G, Ke Y, Zhang Y, Zhang H. Analyzing the cellular and molecular atlas of ovarian mesenchymal cells provides a strategy against female reproductive aging. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2818-2836. [PMID: 37460714 DOI: 10.1007/s11427-022-2335-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 03/22/2023] [Indexed: 12/18/2023]
Abstract
Ovarian mesenchymal cells (oMCs) constitute a distinct microenvironment that supports folliculogenesis under physiological conditions. Supplementation of exogenous non-ovarian mesenchymal-related cells has been reported to be an efficient approach to improve ovarian functions. However, the development and cellular and molecular characteristics of endogenous oMCs remain largely unexplored. In this study, we surveyed the single-cell transcriptomic landscape to dissect the cellular and molecular changes associated with the aging of oMCs in mice. Our results showed that the oMCs were composed of five ovarian differentiated MC (odMC) populations and one ovarian mesenchymal progenitor (oMP) cell population. These cells could differentiate into various odMCs via an oMP-derived route to construct the ovarian stroma structures. Comparative analysis revealed that ovarian aging was associated with decreased quantity of oMP cells and reduced quality of odMCs. Based on the findings of bioinformatics analysis, we designed different strategies involving supplementation with young oMCs to examine their effects on female fertility and health. Our functional investigations revealed that oMCs supplementation prior to ovarian senescence was the optimal method to improve female fertility and extend the reproductive lifespan of aged females in the long-term.
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Affiliation(s)
- Longzhong Jia
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Wenji Wang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
- School of Life Sciences, Taizhou University, Taizhou, 318000, China
| | - Jing Liang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Shudong Niu
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Yibo Wang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Jian Yang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Lingyu Li
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Ge Wang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Xueqiang Xu
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Lu Mu
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Kaixin Cheng
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Xuebing Yang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Yijing Wang
- National Institute of Biological Sciences, Beijing, 102206, China
| | - Haoshu Luo
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Guoliang Xia
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, College of Life Science, Ningxia University, Yinchuan, 750021, China
| | - Yuwen Ke
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
| | - Yan Zhang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
| | - Hua Zhang
- State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
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Ding X, Lv S, Guo Z, Gong X, Wang C, Zhang X, Meng K. Potential Therapeutic Options for Premature Ovarian Insufficiency: Experimental and Clinical Evidence. Reprod Sci 2023; 30:3428-3442. [PMID: 37460850 DOI: 10.1007/s43032-023-01300-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/10/2023] [Indexed: 12/03/2023]
Abstract
Premature ovarian insufficiency (POI) is a condition in which a woman experiences premature decline in ovarian function before the age of 40 years, manifested by menstrual disorders, decreased fertility, and possibly postmenopausal symptoms such as insomnia, hot flashes, and osteoporosis, and is one of the predominant clinical syndromes leading to female infertility. Genetic, immunologic, iatrogenic and other factors, alone or in combination, have been reported to trigger POI, yet the etiology remains unknown in most cases. The main methods currently used clinically to ameliorate menopausal symptoms due to hypoestrogenemia in POI patients are hormone replacement therapy, while the primary methods available to address infertility in POI patients are oocyte donation and cryopreservation techniques, both of which have limitations to some degree. In recent years, researchers have continued to explore more efficient and safe therapies, and have achieved impressive results in preclinical trials. In this article, we will mainly review the three most popular therapies and their related signaling pathways published in the past ten years, with the aim of providing ideas for clinical applications.
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Affiliation(s)
- Xuechun Ding
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China
- College of Second Clinical Medical, Jining Medical University, Jining, China
| | - Shenmin Lv
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China
- College of Second Clinical Medical, Jining Medical University, Jining, China
| | - Zhipeng Guo
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China
- College of Second Clinical Medical, Jining Medical University, Jining, China
| | - Xiaowei Gong
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China
- College of Second Clinical Medical, Jining Medical University, Jining, China
| | - Caiqin Wang
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China
- College of Second Clinical Medical, Jining Medical University, Jining, China
| | - Xiaoyan Zhang
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China
- College of Basic Medicine, Jining Medical University, Jining, China
| | - Kai Meng
- Collaborative Innovation Center for Birth Defect Research and Transformation of Shandong Province, Jining Medical University, Jining, China.
- Lin He's Academician Workstation of New Medicine and Clinical Translation, Jining Medical University, Jining, China.
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Martirosyan YO, Silachev DN, Nazarenko TA, Birukova AM, Vishnyakova PA, Sukhikh GT. Stem-Cell-Derived Extracellular Vesicles: Unlocking New Possibilities for Treating Diminished Ovarian Reserve and Premature Ovarian Insufficiency. Life (Basel) 2023; 13:2247. [PMID: 38137848 PMCID: PMC10744991 DOI: 10.3390/life13122247] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/18/2023] [Accepted: 11/20/2023] [Indexed: 12/24/2023] Open
Abstract
Despite advancements in assisted reproductive technology (ART), achieving successful pregnancy rates remains challenging. Diminished ovarian reserve and premature ovarian insufficiency hinder IVF success-about 20% of in vitro fertilization (IVF) patients face a poor prognosis due to a low response, leading to higher cancellations and reduced birth rates. In an attempt to address the issue of premature ovarian insufficiency (POI), we conducted systematic PubMed and Web of Science research, using keywords "stem cells", "extracellular vesicles", "premature ovarian insufficiency", "diminished ovarian reserve" and "exosomes". Amid the complex ovarian dynamics and challenges like POI, stem cell therapy and particularly the use of extracellular vesicles (EVs), a great potential is shown. EVs trigger paracrine mechanisms via microRNAs and bioactive molecules, suppressing apoptosis, stimulating angiogenesis and activating latent regenerative potential. Key microRNAs influence estrogen secretion, proliferation and apoptosis resistance. Extracellular vesicles present a lot of possibilities for treating infertility, and understanding their molecular mechanisms is crucial for maximizing EVs' therapeutic potential in addressing ovarian disorders and promoting reproductive health.
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Affiliation(s)
- Yana O. Martirosyan
- V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (T.A.N.); (A.M.B.); (P.A.V.); (G.T.S.)
| | - Denis N. Silachev
- V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (T.A.N.); (A.M.B.); (P.A.V.); (G.T.S.)
- Department of Functional Biochemistry of Biopolymers, A.N. Belozersky Research Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, Russia
| | - Tatiana A. Nazarenko
- V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (T.A.N.); (A.M.B.); (P.A.V.); (G.T.S.)
| | - Almina M. Birukova
- V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (T.A.N.); (A.M.B.); (P.A.V.); (G.T.S.)
| | - Polina A. Vishnyakova
- V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (T.A.N.); (A.M.B.); (P.A.V.); (G.T.S.)
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
| | - Gennadiy T. Sukhikh
- V.I. Kulakov National Medical Research Center for Obstetrics Gynecology and Perinatology, Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia; (T.A.N.); (A.M.B.); (P.A.V.); (G.T.S.)
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Zafardoust S, Kazemnejad S, Fathi-Kazerooni M, Darzi M, Sadeghi MR, Sadeghi Tabar A, Sehat Z. The effects of intraovarian injection of autologous menstrual blood-derived mesenchymal stromal cells on pregnancy outcomes in women with poor ovarian response. Stem Cell Res Ther 2023; 14:332. [PMID: 37968668 PMCID: PMC10647057 DOI: 10.1186/s13287-023-03568-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 11/09/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND Assisted reproduction faces a significant obstacle in the form of poor ovarian response (POR) to controlled ovarian stimulation. To address this challenge, mesenchymal stem cell therapy has been proposed as a potential treatment for female infertility and/or restoration of ovarian function in POR women. Our previous research has demonstrated that menstrual blood-derived-mesenchymal stromal cells (MenSCs) injected into the ovaries of women with POR can increase pregnancy rates. The objective of this study was to examine whether MenSC therapy could enhance ovarian reserve parameters and pregnancy outcomes in a larger population of individuals with POR. METHOD This study consisted of 180 infertile individuals with POR who declined oocyte donation. Participants were divided into two groups: those who received bilateral MenSCs intraovarian injection and those who received no intervention. Our primary aim was to compare the rates of spontaneous pregnancy between the two groups, followed by an investigation of any alterations in the ovarian reserve parameters, such as serum FSH, AMH, and AFC levels, as well as the ICSI/IVF outcomes, in both groups of participants. RESULTS The MenSC therapy exhibited a favourable tolerability profile and did not raise any safety concerns. Following the 2-month follow-up period, women who received MenSC treatment demonstrated a significantly higher rate of spontaneous pregnancy (P < 0.005) and an improvement in anti-Müllerian hormone (AMH) levels (P = 0.0007) and antral follicle count (AFC) (P < 0.001), whereas the control group demonstrated a considerable decline in these parameters (Both P < 0.001). The MenSC therapy led to a greater number of mature oocytes and embryos among women who underwent ICSI/IVF. Our age subgroup analysis demonstrated a significant difference in the number of spontaneous pregnancies and ICSI/IVF outcomes between the treatment and control groups only among individuals below 40 years of age. CONCLUSION The results of our study indicate that MenSCs treatment may be a viable option for treating women experiencing POR. However, in order to be widely implemented in clinical practice, the clinical effectiveness of MenSCs therapy will need to be established through rigorous prospective randomized clinical trials. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT05703308. Registered 01/26/2023, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05703308 . IRCT, IRCT20180619040147N4. Registered 08/01/2020.
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Affiliation(s)
- Simin Zafardoust
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
| | - Somaieh Kazemnejad
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | | | - Maryam Darzi
- Avicenna Fertility Clinic, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Mohammad Reza Sadeghi
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Ali Sadeghi Tabar
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Zahra Sehat
- Avicenna Fertility Clinic, Avicenna Research Institute, ACECR, Tehran, Iran
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14
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Cacciottola L, Vitale F, Donnez J, Dolmans MM. Use of mesenchymal stem cells to enhance or restore fertility potential: a systematic review of available experimental strategies. Hum Reprod Open 2023; 2023:hoad040. [PMID: 37954935 PMCID: PMC10637864 DOI: 10.1093/hropen/hoad040] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/15/2023] [Indexed: 11/14/2023] Open
Abstract
STUDY QUESTION To what extent does regenerative medicine with stem cell therapy help to address infertility issues for future clinical application? SUMMARY ANSWER Regenerative medicine using different stem cell sources is yielding promising results in terms of protecting the ovarian reserve from damage and senescence, and improving fertility potential in various preclinical settings. WHAT IS KNOWN ALREADY Regenerative medicine using stem cell therapy is emerging as a potential strategy to address a number of issues in the field of human reproduction. Indeed, different types of adult and fetal mesenchymal stem cells (MSCs) have been tested with promising results, owing to their ability to differentiate into different tissue lineages, move toward specific injured sites (homing), and generate a secretome with wound-healing, proangiogenic, and antioxidant capacities. STUDY DESIGN SIZE DURATION Guided by the checklist for preferred reporting items for systematic reviews and meta-analyses, we retrieved relevant studies from PubMed, Medline, and Embase databases until June 2023 using the following keywords: 'mesenchymal stem cells' AND 'ovarian follicles' OR 'ovarian tissue culture' OR 'ovarian follicle culture' OR 'cumulus oocyte complex'. Only peer-reviewed published articles written in English were included. PARTICIPANTS/MATERIALS SETTING METHODS The primary outcome for the experimental strategies was evaluation of the ovarian reserve, with a focus on follicle survival, number, and growth. Secondary outcomes involved analyses of other parameters associated with the follicle pool, such as hormones and growth factors, ovarian tissue viability markers including oxidative stress levels, oocyte growth and maturation rates, and of course pregnancy outcomes. MAIN RESULTS AND THE ROLE OF CHANCE Preclinical studies exploring MSCs from different animal origins and tissue sources in specific conditions were selected (n = 112), including: in vitro culture of granulosa cells, ovarian tissue and isolated ovarian follicles; ovarian tissue transplantation; and systemic or intraovarian injection after gonadotoxic or age-related follicle pool decline. Protecting the ovarian reserve from aging and gonadotoxic damage has been widely tested in vitro and in vivo using murine models and is now yielding initial data in the first ever case series of patients with premature ovarian insufficiency. Use of MSCs as feeder cells in ovarian tissue culture was found to improve follicle outcomes and oocyte competence, bringing us one step closer to future clinical application. MSCs also have proved effective at boosting revascularization in the transplantation site when grafting ovarian tissue in experimental animal models. LIMITATIONS REASONS FOR CAUTION While preclinical results look promising in terms of protecting the ovarian reserve in different experimental models (especially those in vitro using various mammal experimental models and in vivo using murine models), there is still a lot of work to do before this approach can be considered safe and successfully implemented in a clinical setting. WIDER IMPLICATIONS OF THE FINDINGS All gathered data on the one hand show that regenerative medicine techniques are quickly gaining ground among innovative techniques being developed for future clinical application in the field of reproductive medicine. After proving MSC effectiveness in preclinical settings, there is still a lot of work to do before MSCs can be safely and effectively used in different clinical applications. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (FNRS-PDR T.0077.14, FNRS-CDR J.0063.20, and grant 5/4/150/5 awarded to Marie-Madeleine Dolmans), Fonds Spéciaux de Recherche, and the Fondation St Luc. None of the authors have any competing interest to disclose. REGISTRATION NUMBER N/A.
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Affiliation(s)
- L Cacciottola
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - F Vitale
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - J Donnez
- Society for Research into Infertility, Brussels, Belgium
- Université Catholique de Louvain, Brussels, Belgium
| | - M M Dolmans
- Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
- Department of Gynecology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
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15
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Adriansyah RF, Margiana R, Supardi S, Narulita P. Current Progress in Stem Cell Therapy for Male Infertility. Stem Cell Rev Rep 2023; 19:2073-2093. [PMID: 37440145 DOI: 10.1007/s12015-023-10577-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2023] [Indexed: 07/14/2023]
Abstract
Infertility has become one of the most common issues worldwide, which has negatively affected society and infertile couples. Meanwhile, male infertility is responsible for about 50% of infertility. Accordingly, a great number of researchers have focused on its treatment during the last few years; however, current therapies such as assisted reproductive technology (ART) are not effective enough in treating male infertility. Because of their self-renewal and differentiation capabilities and unlimited sources, stem cells have recently raised great hope in the treatment of reproductive system disorders. Stem cells are undifferentiated cells that can induce different numbers of specific cells, such as male and female gametes, demonstrating their potential application in the treatment of infertility. The present review aimed at identifying the causes and potential factors that influence male fertility. Besides, we highlighted the recent studies that investigated the efficiency of stem cells such as spermatogonial stem cells (SSCs), embryonic stem cells (ESCs), very small embryonic-like stem cells (VSELs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs) in the treatment of various types of male infertility.
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Affiliation(s)
| | - Ria Margiana
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Indonesia General Academic Hospital, Depok, Indonesia.
- Ciptomangunkusumo General Academic Hospital, Jakarta, Indonesia.
| | - Supardi Supardi
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Pety Narulita
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
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16
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Moustaki M, Kontogeorgi A, Tsangkalova G, Tzoupis H, Makrigiannakis A, Vryonidou A, Kalantaridou SN. Biological therapies for premature ovarian insufficiency: what is the evidence? FRONTIERS IN REPRODUCTIVE HEALTH 2023; 5:1194575. [PMID: 37744287 PMCID: PMC10512839 DOI: 10.3389/frph.2023.1194575] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 08/22/2023] [Indexed: 09/26/2023] Open
Abstract
Premature Ovarian Insufficiency (POI) is a multi-factorial disorder that affects women of reproductive age. The condition is characterized by the loss of ovarian function before the age of 40 years and several factors have been identified to be implicated in its pathogenesis. Remarkably though, at least 50% of women have remaining follicles in their ovaries after the development of ovarian insufficiency. Population data show that approximately up to 3.7% of women worldwide suffer from POI and subsequent infertility. Currently, the treatment of POI-related infertility involves oocyte donation. However, many women with POI desire to conceive with their own ova. Therefore, experimental biological therapies, such as Platelet-Rich Plasma (PRP), Exosomes (exos) therapy, In vitro Activation (IVA), Stem Cell therapy, MicroRNAs and Mitochondrial Targeting Therapies are experimental treatment strategies that focus on activating oogenesis and folliculogenesis, by upregulating natural biochemical pathways (neo-folliculogenesis) and improving ovarian microenvironment. This mini-review aims at identifying the main advantages of these approaches and exploring whether they can underpin existing assisted reproductive technologies.
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Affiliation(s)
- Melpomeni Moustaki
- Department of Endocrinology and Diabetes Center, Hellenic Red Cross Hospital, Athens, Greece
| | | | | | | | - Antonis Makrigiannakis
- Department of Obstetrics and Gynecology, University of Crete Medical School, Heraklion, Greece
| | - Andromachi Vryonidou
- Department of Endocrinology and Diabetes Center, Hellenic Red Cross Hospital, Athens, Greece
| | - Sophia N. Kalantaridou
- Serum IVF Fertility Center, Athens, Greece
- 3rd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
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17
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Rizano A, Margiana R, Supardi S, Narulita P. Exploring the future potential of mesenchymal stem/stromal cells and their derivatives to support assisted reproductive technology for female infertility applications. Hum Cell 2023; 36:1604-1619. [PMID: 37407748 DOI: 10.1007/s13577-023-00941-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/16/2023] [Indexed: 07/07/2023]
Abstract
Women's infertility impacts the quality of life of both patients and couples and has multifaceted dimensions that increase the number of challenges associated with female infertility and how to face them. Female reproductive disorders, such as premature ovarian failure (POF), endometriosis, Asherman syndrome (AS), polycystic ovary syndrome (PCOS), and preeclampsia, can stimulate infertility. In the last decade, translational medicine has advanced, and scientists are focusing on infertility therapy with innovative attitudes. Recent investigations have suggested that stem cell treatments could be safe and effective. Stem cell therapy has established a novel method for treating women's infertility as part of a regeneration approach. The chief properties and potential of mesenchymal stem/stromal cells (MSCs) in the future of women's infertility should be considered by researchers. Due to their high abundance, great ability to self-renew, and high differentiation capacity, as well as less ethical concerns, MSC-based therapy has been found to be an effective alternative strategy to the previous methods for treating female infertility, such as intrauterine insemination, in vitro fertilization, medicines, and surgical procedures. These types of stem cells exert their beneficial role by releasing active mediators, promoting cell homing, and contributing to immune modulation. Here we first provide an overview of MSCs and their crucial roles in both biological and immunological processes. The next large chapter covers current preclinical and clinical studies on the application of MSCs to treat various female reproductive disorders. Finally, we deliberate on the extant challenges that hinder the application of MSCs in female infertility and suggest plausible measures to alleviate these impediments.
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Affiliation(s)
- Andrew Rizano
- Department of Medical Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Ria Margiana
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Indonesia General Academic Hospital, Depok, Indonesia.
- Ciptomangunkusumo General Academic Hospital, Jakarta, Indonesia.
| | - Supardi Supardi
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Pety Narulita
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
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Wu J, Shi Y, Yang S, Tang Z, Li Z, Li Z, Zuo J, Ji W, Niu Y. Current state of stem cell research in non-human primates: an overview. MEDICAL REVIEW (2021) 2023; 3:277-304. [PMID: 38235400 PMCID: PMC10790211 DOI: 10.1515/mr-2023-0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/04/2023] [Indexed: 01/19/2024]
Abstract
The remarkable similarity between non-human primates (NHPs) and humans establishes them as essential models for understanding human biology and diseases, as well as for developing novel therapeutic strategies, thereby providing more comprehensive reference data for clinical treatment. Pluripotent stem cells such as embryonic stem cells and induced pluripotent stem cells provide unprecedented opportunities for cell therapies against intractable diseases and injuries. As continue to harness the potential of these biotechnological therapies, NHPs are increasingly being employed in preclinical trials, serving as a pivotal tool to evaluate the safety and efficacy of these interventions. Here, we review the recent advancements in the fundamental research of stem cells and the progress made in studies involving NHPs.
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Affiliation(s)
- Junmo Wu
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Yuxi Shi
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Shanshan Yang
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Zengli Tang
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Zifan Li
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Zhuoyao Li
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Jiawei Zuo
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Weizhi Ji
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
| | - Yuyu Niu
- Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Kunming, Yunnan Province, China
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Guo C, Ma Y, Situ Y, Liu L, Luo G, Li H, Ma W, Sun L, Wang W, Weng Q, Wu L, Fan D. Mesenchymal stem cells therapy improves ovarian function in premature ovarian failure: a systematic review and meta-analysis based on preclinical studies. Front Endocrinol (Lausanne) 2023; 14:1165574. [PMID: 37484938 PMCID: PMC10361781 DOI: 10.3389/fendo.2023.1165574] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 06/12/2023] [Indexed: 07/25/2023] Open
Abstract
Background Studies have revealed that the transplantation of mesenchymal stem cells (MSCs) might be a potential star candidate for premature ovarian failure (POF) in animal experiments. However, individual studies with a small sample size cannot be used to draw a clear conclusion. Therefore, we conducted a systematic review and meta-analysis to explore the potential of using MSCs in the treatment of POF in animals. Methods Seven databases were searched for studies exploring the effect of the transplantation of MSCs on POF in animal models. The PRISMA guideline was followed, and the methodological quality was ensured using SYRCLE's risk of bias tool. RevMan 5.4 and STATA 12.0 software was performed to meta-analysis. Results In total, 37 studies involving 1,079 animals were included. Significant associations were found for MSCs with the levels of E2 (SMD 2.69 [95% CI 1.97, 3.41]), FSH (-2.02, [-2.74, -1.30]), primary follicles (2.04, [1.17, 2.92]), secondary follicles (1.93, [1.05, 2.81]), and primordial follicles (2.38, [1.19, 3.57]. Other outcomes, such as AMH, LH, INHB, antral follicles, growing follicles, mature follicles, and early antral were also found to be significant. There was no difference in FSH/LH, corpus leteum, follicles, and estruc cycle. Conclusions Our meta-analysis result indicated that the transplantation of MSCs might exert therapeutic effects on animal models of POF, and these effects might be associated with improving the disorder of the sexual cycle, modulating serum hormone expressions to a better state, and restoring ovarian function.
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Affiliation(s)
- Congcong Guo
- Reproductive Medicine Center, Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Yanqiu Situ
- Reproductive Medicine Center, Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Li Liu
- Department of Library, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Guoqun Luo
- Reproductive Medicine Center, Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Huan Li
- Reproductive Medicine Center, Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Wenmin Ma
- Reproductive Medical Center, Zhaoqing Westriver Hospital, Zhaoqing, Guangdong, China
| | - Li Sun
- Department of Library, Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Wen Wang
- Department of Obstetrics, Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Qiuying Weng
- Reproductive Medicine Center, Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Linlin Wu
- Department of Obstetrics, Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Dazhi Fan
- Department of Obstetrics, Foshan Women and Children Hospital, Foshan, Guangdong, China
- Foshan Institute of Fetal Medicine, Foshan Women and Children Hospital, Foshan, Guangdong, China
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20
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Ai G, Meng M, Guo J, Li C, Zhu J, Liu L, Liu B, Yang W, Shao X, Cheng Z, Wang L. Adipose-derived stem cells promote the repair of chemotherapy-induced premature ovarian failure by inhibiting granulosa cells apoptosis and senescence. Stem Cell Res Ther 2023; 14:75. [PMID: 37038203 PMCID: PMC10088140 DOI: 10.1186/s13287-023-03297-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 03/23/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Chemotherapeutic drugs, particularly alkylating cytotoxics such as cyclophosphamide (CTX), play an important role to induce premature ovarian failure (POF). Hormone replacement therapy (HRT) is a widely used treatment to improve hormone secretion. However, the long-term HRT increases the risk of breast cancer and cardiovascular disease are attracting concerns. Therefore, there is an urgent need to develop a safe and effective treatment for POF. METHOD Adipose-derived stem cells (ADSCs) were isolated and identified from human adipose tissue. For POF modeling, CTX were intraperitoneal injected into CTX-acute group, CTX-chronic group, CTX-acute + ADSCs group and CTX-chronic + ADSCs group rats; For transplantation, ADSCs were transplanted into POF rats through tail-vein. The control group rats were injected with PBS. The effects of POF modeling and transplantation were determined by estrous cycle analysis, histopathological analysis, immunohistochemical staining and apoptosis-related marker. To evaluate the effects of ADSC on granulosa cells in vitro, CTX-induced senescent KGN cells were co-cultured with ADSCs, and senescent-related marker expression was investigated by immunofluorescent staining. RESULTS In vivo studies revealed that ADSCs transplantation reduced the apoptosis of ovarian granulosa cells and secretion of follicle-stimulating hormone. The number of total follicles, primordial follicles, primary follicles, and mature follicles and secretion of anti-Müllerian hormone and estradiol (E2) were also increased by ADSCs. The estrous cycle was also improved by ADSC transplantation. Histopathological analysis showed that CTX-damaged ovarian microenvironment was improved by ADSCs. Furthermore, TUNEL staining indicated that apoptosis of granulosa cells was decreased by ADSCs. In vitro assay also demonstrated that ADSC markedly attenuated CTX-induced senescence and apoptosis of granulosa cell. Mechanistically, both in vivo and in vitro experiments proved that ADSC transplantation suppressed activation of the PI3K/Akt/mTOR axis. CONCLUSION Our experiment demonstrated that a single injection of high-dose CTX was a less damaging chemotherapeutic strategy than continuous injection of low-dose CTX, and tail-vein injection of ADSCs was a potential approach to promote the restoration of CTX-induced POF.
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Affiliation(s)
- Guihai Ai
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Meng Meng
- Department of Gynecology and Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China
| | - Jing Guo
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Caixia Li
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jihui Zhu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Li Liu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Biting Liu
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Wenhan Yang
- Department of Gynecology and Obstetrics, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China
| | - Xiaowen Shao
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhongping Cheng
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Tongji University School of Medicine, Shanghai, 200092, China.
| | - Lian Wang
- Department of Gynecology and Obstetrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Gynecologic Minimally Invasive Surgery Research Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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Liu X, Li J, Wang W, Ren X, Hu JF. Therapeutic restoration of female reproductive and endocrine dysfunction using stem cells. Life Sci 2023; 322:121658. [PMID: 37023951 DOI: 10.1016/j.lfs.2023.121658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/30/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023]
Abstract
Millions of women worldwide suffer from infertility associated with gynecologic disorders such as premature ovarian insufficiency, polycystic ovary syndrome, Asherman syndrome, endometriosis, preeclampsia, and fallopian tube obstruction. These disorders can lead to infertility and thereby affect the quality of life of the infertile couple because of their psychological impact and significant costs. In recent years, stem cell therapy has emerged as a therapeutic approach to repair or replace damaged tissues or organs. This review describes the recent development as well as the underlying mechanisms of stem cell therapy for a variety of female reproductive diseases, offering us new therapeutic options for the treatment of female reproductive and endocrine dysfunction.
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Affiliation(s)
- Xiaobo Liu
- The Laboratory of Cancer Precision Medicine, the First Hospital of Jilin University, Changchun, Jilin 130061, China
| | - Jiajia Li
- The Laboratory of Cancer Precision Medicine, the First Hospital of Jilin University, Changchun, Jilin 130061, China; Department of Gynecologic Oncology, Gynecology and Obstetrics Centre, the First Hospital of Jilin University, Changchun, Jilin 130012, China
| | - Wenjun Wang
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin 130061, China; Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA
| | - Xue Ren
- Department of Gynecologic Oncology, Gynecology and Obstetrics Centre, the First Hospital of Jilin University, Changchun, Jilin 130012, China
| | - Ji-Fan Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin 130061, China; Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
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22
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Geng Z, Guo H, Li Y, Liu Y, Zhao Y. Stem cell-derived extracellular vesicles: A novel and potential remedy for primary ovarian insufficiency. Front Cell Dev Biol 2023; 11:1090997. [PMID: 36875770 PMCID: PMC9977284 DOI: 10.3389/fcell.2023.1090997] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/06/2023] [Indexed: 02/17/2023] Open
Abstract
Primary ovarian insufficiency (POI) is an essential cause of young female fertility loss. At present, there are many treatments for primary ovarian insufficiency, but due to the complexity of the pathogenesis of primary ovarian insufficiency, the efficacy still could not be satisfactory. Stem cell transplantation is a feasible intervention protocol for primary ovarian insufficiency. However, its wide application in the clinic is limited by some defects such as tumorigenic and controversial ethical issues. Stem cell-derived extracellular vesicles (EVs) represent an important mode of intercellular communication attracting increasing interest. It is well documented that stem cell-derived extracellular vesicles for primary ovarian insufficiency with exciting therapeutic effects. Studies have found that stem cell-derived extracellular vesicles could improve ovarian reserve, increase the growth of follicles, reduce follicle atresia, and restore hormone levels of FSH and E2. Its mechanisms include inhibiting ovarian granulosa cells (GCs) apoptosis, reactive oxygen species, and inflammatory response and promoting granulosa cells proliferation and angiogenesis. Thus, stem cell-derived extracellular vesicles are a promising and potential method for primary ovarian insufficiency patients. However, stem cell-derived extracellular vesicles are still a long way from clinical translation. This review will provide an overview of the role and the mechanisms of stem cell-derived extracellular vesicles in primary ovarian insufficiency, and further elaborate on the current challenges. It may suggest new directions for future research.
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Affiliation(s)
- Zixiang Geng
- Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Hailing Guo
- Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Yifei Li
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Liu
- Department of Dermatology, Shanghai Songjiang District Central Hospital, Shanghai, China
| | - Yongfang Zhao
- Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
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Zafardoust S, Kazemnejad S, Darzi M, Fathi-Kazerooni M, Saffarian Z, Khalili N, Edalatkhah H, Mirzadegan E, Khorasani S. Intraovarian Administration of Autologous Menstrual Blood Derived-Mesenchymal Stromal Cells in Women with Premature Ovarian Failure. Arch Med Res 2023; 54:135-144. [PMID: 36702667 DOI: 10.1016/j.arcmed.2022.12.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 11/12/2022] [Accepted: 12/20/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND Premature ovarian failure (POF) is a well-known cause of infertility, particularly in women under the age of 40. POF is also associated with elevated gonadotropin levels, amenorrhea and sex-hormone deficiency. AIM OF THE STUDY In this study, the therapeutic potential of autologous mesenchymal stromal cells obtained from menstrual blood (Men-MSCs) for patients with POF was evaluated. METHODS 15 POF patients were included in the study. The cultured Men-MSCs were confirmed by flow cytometry, karyotype, endotoxin and mycoplasma and were then injected into the patients' right ovary by vaginal ultrasound guidance and under general anesthesia and aseptic conditions. Changes in patients' anti-Müllerian hormone (AMH), antral follicle count (AFC), follicle-stimulating hormone (FSH), luteal hormone (LH), and estradiol (E2) levels, as well as general flushing and vaginal dryness were followed up to one year after treatment. RESULTS All patients were satisfied with a decrease in general flushing and vaginal dryness. 4 patients (2.9%) showed a spontaneous return of menstruation without additional pharmacological treatment. There was a significant difference in AFC (0 vs. 1 ± 0.92 count, p value ≤0.001%), FSH (74 ± 22.9 vs. 54.8 ± 17.5 mIU/mL, p-value ≤0.05%), E2 (10.2 ± 6 vs. 21.8 ± 11.5 pg/mL p-value ≤0.01%), LH (74 ± 22.9 vs. 54.8 ± 17.5 IU/L,p-value ≤0.01%) during 3 months post-injection. However, there were no significant changes in AMH (p-value ≥0.05%). There were also no significant differences in assessed parameters between 3 and 6 months after cell injection. CONCLUSION According to the findings of this study, administration of Men-MSCs improved ovarian function and menstrual restoration in some POF patients.
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Affiliation(s)
- Simin Zafardoust
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Somaieh Kazemnejad
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
| | - Maryam Darzi
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Mina Fathi-Kazerooni
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Zahra Saffarian
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Niloofar Khalili
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Haleh Edalatkhah
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Ebrahim Mirzadegan
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Somayeh Khorasani
- Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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24
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Mohamed Rasheed ZB, Nordin F, Wan Kamarul Zaman WS, Tan YF, Abd Aziz NH. Autologous Human Mesenchymal Stem Cell-Based Therapy in Infertility: New Strategies and Future Perspectives. BIOLOGY 2023; 12:108. [PMID: 36671799 PMCID: PMC9855776 DOI: 10.3390/biology12010108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/06/2023] [Accepted: 01/08/2023] [Indexed: 01/12/2023]
Abstract
Infertility could be associated with a few factors including problems with physical and mental health, hormonal imbalances, lifestyles, and genetic factors. Given that there is a concern about the rise of infertility globally, increased focus has been given to its treatment for the last several decades. Traditional assisted reproductive technology (ART) has been the prime option for many years in solving various cases of infertility; however, it contains significant risks and does not solve the fundamental problem of infertility such as genetic disorders. Attention toward the utilization of MSCs has been widely regarded as a promising option in the development of stem-cell-based infertility treatments. This narrative review briefly presents the challenges in the current ART treatment of infertility and the various potential applications of autologous MSCs in the treatment of these reproductive diseases.
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Affiliation(s)
- Zahirrah Begam Mohamed Rasheed
- UKM Medical Molecular Biology Institute (UMBI), Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
| | - Fazlina Nordin
- Centre for Tissue Engineering and Regenerative Medicine (CTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia
| | | | - Yuen-Fen Tan
- PPUKM-MAKNA Cancer Center, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, WPKL, Kuala Lumpur 56000, Malaysia
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Sungai Long Campus, Bandar Sungai Long, Kajang 43000, Malaysia
| | - Nor Haslinda Abd Aziz
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
- Research Laboratory of UKM Specialist Children’s Hospital, UKM Specialist Children’s Hospital, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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25
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Babaei K, Aziminezhad M, Norollahi SE, Vahidi S, Samadani AA. Cell therapy for the treatment of reproductive diseases and infertility: an overview from the mechanism to the clinic alongside diagnostic methods. Front Med 2022; 16:827-858. [PMID: 36562947 DOI: 10.1007/s11684-022-0948-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/28/2022] [Indexed: 12/24/2022]
Abstract
Infertility is experienced by 8%-12% of adults in their reproductive period globally and has become a prevalent concern. Besides routine therapeutic methods, stem cells are rapidly being examined as viable alternative therapies in regenerative medicine and translational investigation. Remarkable progress has been made in understanding the biology and purpose of stem cells. The affected pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) are further studied for their possible use in reproductive medicine, particularly for infertility induced by premature ovarian insufficiency and azoospermia. Accordingly, this study discusses current developments in the use of some kinds of MSCs such as adipose-derived stem cells, bone marrow stromal cells, umbilical cord MSCs, and menstrual blood MSCs. These methods have been used to manage ovarian and uterine disorders, and each technique presents a novel method for the therapy of infertility.
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Affiliation(s)
- Kosar Babaei
- Non-Communicable Disease Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Mohsen Aziminezhad
- Non-Communicable Disease Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.,UMR INSERM U 1122, IGE-PCV, Interactions Gène-Environment En Physiopathologie Cardiovascular Université De Lorraine, Nancy, France
| | - Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran.
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26
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Huang Y, Zhu M, Liu Z, Hu R, Li F, Song Y, Geng Y, Ma W, Song K, Zhang M. Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects. Front Immunol 2022; 13:997808. [PMID: 36389844 PMCID: PMC9646528 DOI: 10.3389/fimmu.2022.997808] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/17/2022] [Indexed: 12/31/2022] Open
Abstract
Premature ovarian failure (POF) is a common female reproductive disorder and characterized by menopause, increased gonadotropin levels and estrogen deficiency before the age of 40 years old. The etiologies and pathogenesis of POF are not fully clear. At present, hormone replacement therapy (HRT) is the main treatment options for POF. It helps to ameliorate perimenopausal symptoms and related health risks, but can't restore ovarian function and fertility fundamentally. With the development of regenerative medicine, bone marrow mesenchymal stem cells (BMSCs) have shown great potential for the recovery of ovarian function and fertility based on the advantages of abundant sources, high capacity for self-renewal and differentiation, low immunogenicity and less ethical considerations. This systematic review aims to summarize the possible therapeutic mechanisms of BMSCs for POF. A detailed search strategy of preclinical studies and clinical trials on BMSCs and POF was performed on PubMed, MEDLINE, Web of Science and Embase database. A total of 21 studies were included in this review. Although the standardization of BMSCs need more explorations, there is no doubt that BMSCs transplantation may represent a prospective therapy for POF. It is hope to provide a theoretical basis for further research and treatment for POF.
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Affiliation(s)
- Yanjing Huang
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengdi Zhu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhuo Liu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Runan Hu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fan Li
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yufan Song
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuli Geng
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenwen Ma
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kunkun Song
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Mingmin Zhang, ; Kunkun Song,
| | - Mingmin Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Mingmin Zhang, ; Kunkun Song,
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27
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Hoang VT, Nguyen HP, Nguyen VN, Hoang DM, Nguyen TST, Nguyen Thanh L. “Adipose-derived mesenchymal stem cell therapy for the management of female sexual dysfunction: Literature reviews and study design of a clinical trial”. Front Cell Dev Biol 2022; 10:956274. [PMID: 36247008 PMCID: PMC9554747 DOI: 10.3389/fcell.2022.956274] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/29/2022] [Indexed: 11/25/2022] Open
Abstract
Hormone imbalance and female sexual dysfunction immensely affect perimenopausal female health and quality of life. Hormone therapy can improve female hormone deficiency, but long-term use increases the risk of cardiovascular diseases and cancer. Therefore, it is necessary to develop a novel effective treatment to achieve long-term improvement in female general and sexual health. This study reviewed factors affecting syndromes of female sexual dysfunction and its current therapy options. Next, the authors introduced research data on mesenchymal stromal cell/mesenchymal stem cell (MSC) therapy to treat female reproductive diseases, including Asherman’s syndrome, premature ovarian failure/primary ovarian insufficiency, and vaginal atrophy. Among adult tissue-derived MSCs, adipose tissue-derived stem cells (ASCs) have emerged as the most potent therapeutic cell therapy due to their abundant presence in the stromal vascular fraction of fat, high proliferation capacity, superior immunomodulation, and strong secretion profile of regenerative factors. Potential mechanisms and side effects of ASCs for the treatment of female sexual dysfunction will be discussed. Our phase I clinical trial has demonstrated the safety of autologous ASC therapy for women and men with sexual hormone deficiency. We designed the first randomized controlled crossover phase II trial to investigate the safety and efficacy of autologous ASCs to treat female sexual dysfunction in perimenopausal women. Here, we introduce the rationale, trial design, and methodology of this clinical study. Because aging and metabolic diseases negatively impact the bioactivity of adult-derived MSCs, this study will use ASCs cultured in physiological oxygen tension (5%) to cope with these challenges. A total of 130 perimenopausal women with sexual dysfunction will receive two intravenous infusions of autologous ASCs in a crossover design. The aims of the proposed study are to evaluate 1) the safety of cell infusion based on the frequency and severity of adverse events/serious adverse events during infusion and follow-up and 2) improvements in female sexual function assessed by the Female Sexual Function Index (FSFI), the Utian Quality of Life Scale (UQOL), and the levels of follicle-stimulating hormone (FSH) and estradiol. In addition, cellular aging biomarkers, including plasminogen activator inhibitor-1 (PAI-1), p16 and p21 expression in T cells and the inflammatory cytokine profile, will also be characterized. Overall, this study will provide essential insights into the effects and potential mechanisms of ASC therapy for perimenopausal women with sexual dysfunction. It also suggests direction and design strategies for future research.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Hoang-Phuong Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Viet Nhan Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
| | - Duc M. Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
| | - Tan-Sinh Thi Nguyen
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, Hanoi, Vietnam
- Vinmec International Hospital—Times City, Vinmec Health Care System, Hanoi, Vietnam
- College of Health Science, Vin University, Vinhomes Ocean Park, Hanoi, Vietnam
- *Correspondence: Liem Nguyen Thanh,
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Tahmasbpour Marzouni E, Stern C, Henrik Sinclair A, Tucker EJ. Stem Cells and Organs-on-chips: New Promising Technologies for Human Infertility Treatment. Endocr Rev 2022; 43:878-906. [PMID: 34967858 DOI: 10.1210/endrev/bnab047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Indexed: 11/19/2022]
Abstract
Having biological children remains an unattainable dream for most couples with reproductive failure or gonadal dysgenesis. The combination of stem cells with gene editing technology and organ-on-a-chip models provides a unique opportunity for infertile patients with impaired gametogenesis caused by congenital disorders in sex development or cancer survivors. But how will these technologies overcome human infertility? This review discusses the regenerative mechanisms, applications, and advantages of different types of stem cells for restoring gametogenesis in infertile patients, as well as major challenges that must be overcome before clinical application. The importance and limitations of in vitro generation of gametes from patient-specific human-induced pluripotent stem cells (hiPSCs) will be discussed in the context of human reproduction. The potential role of organ-on-a-chip models that can direct differentiation of hiPSC-derived primordial germ cell-like cells to gametes and other reproductive organoids is also explored. These rapidly evolving technologies provide prospects for improving fertility to individuals and couples who experience reproductive failure.
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Affiliation(s)
- Eisa Tahmasbpour Marzouni
- Laboratory of Regenerative Medicine & Biomedical Innovations, Pasteur Institute of Iran, Tehran, Iran
| | - Catharyn Stern
- Royal Women's Hospital, Parkville and Melbourne IVF, Melbourne, Australia
| | - Andrew Henrik Sinclair
- Reproductive Development, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia
| | - Elena Jane Tucker
- Reproductive Development, Murdoch Children's Research Institute, Melbourne, Australia.,Department of Paediatrics, University of Melbourne, Melbourne, Australia
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29
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Huang QY, Chen SR, Zhao YX, Chen JM, Chen WH, Lin S, Shi QY. Melatonin enhances autologous adipose-derived stem cells to improve mouse ovarian function in relation to the SIRT6/NF-κB pathway. Stem Cell Res Ther 2022; 13:399. [PMID: 35927704 PMCID: PMC9351187 DOI: 10.1186/s13287-022-03060-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
Background Premature ovarian insufficiency (POI) is the main cause of female infertility. Adipose-derived stem cells (ADSCs) are ideal candidates for the treatment of POI. However, some deficient biological characteristics of ADSCs limit their utility. This study investigated whether melatonin (MLT)-pretreated autologous ADSCs were superior to ADSCs alone in the treatment of the POI mouse model. Methods Autologous ADSCs were isolated and cultured in MLT-containing medium. Surface markers of ADSCs were detected by flow cytometry. To determine the effect of MLT on ADSCs, CCK-8 assay was used to detect ADSCs proliferation and enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of cytokines. The POI model was established by intraperitoneal injection of cyclophosphamide and busulfan. Then, MLT-pretreated autologous ADSCs were transplanted into mice by intraovarian injection. After 7 days of treatment, ovarian morphology, follicle counts, and sex hormones levels were evaluated by hematoxylin and eosin (H&E) staining and ELISA, and the recovery of fertility was also observed. The expressions of SIRT6 and NF-κB were detected by immunohistochemical (IHC) staining and quantitative real-time polymerase chain reaction (qRT-PCR). Results Flow cytometry showed that autologous ADSCs expressed CD90 (99.7%) and CD29 (97.5%). MLT can not only promote the proliferation of ADSCs but also boost their secretory function, especially when ADSCs were pretreated with 5 µM MLT for 3 days, improving the interference effect. After transplantation of autologous ADSCs pretreated with 5 µM MLT, the serum hormone levels and reproductive function were significantly recovered, and the mean counts of primordial follicle increased. At the same time, the expression of SIRT6 was remarkably increased and the expression of NF-κB was significantly decreased in this group. Conclusions MLT enhances several effects of ADSCs in restoring hormone levels, mean primordial follicle counts, and reproductive capacity in POI mice. Meanwhile, our results suggest that the SIRT6/NF-κB signal pathway may be the potential therapeutic mechanism for ADSCs to treat POI.
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Affiliation(s)
- Qiao-Yi Huang
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Shao-Rong Chen
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Yun-Xia Zhao
- Department of Gynaecology and Obstetrics, University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Jia-Ming Chen
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Wei-Hong Chen
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China. .,Group of Neuroendocrinology, Garvan Institute of Medical Research, 384 Victoria St, Sydney, Australia.
| | - Qi-Yang Shi
- Department of Gynaecology and Obstetrics, Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China.
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30
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Wu M, Huang Y, Zhu Q, Zhu X, Xue L, Xiong J, Chen Y, Wu C, Guo Y, Li Y, Wu M, Wang S. Adipose tissue and ovarian aging: Potential mechanism and protective strategies. Ageing Res Rev 2022; 80:101683. [PMID: 35817297 DOI: 10.1016/j.arr.2022.101683] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/29/2022] [Accepted: 07/05/2022] [Indexed: 11/01/2022]
Abstract
Ovarian aging occurs approximately 10 years prior to the natural age-associated functional decline of other organ systems. With the increase of life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Therefore, understanding the causes and molecular mechanisms of ovarian aging is very essential for the inhibition of age-related diseases and the promotion of health and longevity in women. Recently, studies have revealed an association between adipose tissue (AT) and ovarian aging. Alterations in the function and quantity of AT have profound consequences on ovarian function because AT is central for follicular development, lipid metabolism, and hormonal regulation. Moreover, the interplay between AT and the ovary is bidirectional, with ovary-derived signals directly affecting AT biology. In this review, we summarize the current knowledge of the complex molecular mechanisms controlling the crosstalk between the AT and ovarian aging, and further discuss how therapeutic targeting of the AT can delay ovarian aging.
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Affiliation(s)
- Meng Wu
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Yibao Huang
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Qingqing Zhu
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Xiaoran Zhu
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Liru Xue
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Jiaqiang Xiong
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Ying Chen
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Chuqing Wu
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Yican Guo
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Yinuo Li
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China
| | - Mingfu Wu
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China.
| | - Shixuan Wang
- National Clinical Research Center for Obstetrical and Gynecological Diseases; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China; National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei 430030, China.
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Kuang X, Tang Y, Xu H, Ji M, Lai D. The Evaluation of Ovarian Function Recovery Following Treatment of Primary Ovarian Insufficiency: A Systematic Review. Front Endocrinol (Lausanne) 2022; 13:855992. [PMID: 35573993 PMCID: PMC9095968 DOI: 10.3389/fendo.2022.855992] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 03/28/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Primary ovarian insufficiency (POI) is gaining awareness as its prevalence increases and its effect on patients is extremely negative. To date, several therapies have been designed to treat POI, but the conclusions are conflicting, in part, due to inconsistent evaluation methods. Thus, we explore a multi-index of ovarian function assessment methods to evaluate the recovery of ovarian function after various therapies in order to evaluate effectiveness in a more comprehensive manner. AIM The purpose of this review is to assess the effectiveness of various therapies to recover ovarian function in patients with POI. The primary outcome measures were anti-Müllerian hormone (AMH) levels, follicle stimulating hormone (FSH) levels, and antral follicle count (AFC). The secondary outcomes included the change of mean ovarian volume, menstruation recovery, and pregnancy rate. METHODS Our systematic searching including PubMed, Web of Science, Cochrane, and Embase databases was conducted to find all human clinical trial articles published from January 2000 to April 2021 and related to POI treatment, including the keywords: POI, AFC, and hormones. All prospective and retrospective studies exploring ovarian function recovery that include AFC, AMH levels, and FSH levels evolution throughout treatment were included. All patients included in the studies met the POI criteria described by the European Society for Human Reproductive Embryology (ESHRE) guideline. RESULTS Six studies were selected based on the criteria: one randomized controlled trial and five observational studies. Among them, two studies focused on the intraovarian platelet-rich plasma (PRP) infusion treatment, two studies focused on dehydroepiandrosterone (DHEA) supplements, one study focused on hormone replacement therapy (HRT), and one study focused on autologous adipose-derived stromal cells (ADSCs) treatment. There was insufficient scientific evidence that any approach could help ovarian function recovery in patients with POI because the ovarian function markers in each study had inconsistent changes with 26 patients (6.2%) reporting spontaneous pregnancy. CONCLUSION Serum AMH levels, FSH levels, and AFC are sensitive indicators and reflect the evolution of ovarian function. Large randomized controlled trials are necessary, and the data on ovarian function should be collected comprehensively to evaluate the effectiveness of a variety of treatments.
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Affiliation(s)
- Xiaojun Kuang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yongzhe Tang
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
| | - Hong Xu
- School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Min Ji
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- *Correspondence: Min Ji, ; Dongmei Lai,
| | - Dongmei Lai
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
- *Correspondence: Min Ji, ; Dongmei Lai,
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Wang J, Liu W, Yu D, Yang Z, Li S, Sun X. Research Progress on the Treatment of Premature Ovarian Failure Using Mesenchymal Stem Cells: A Literature Review. Front Cell Dev Biol 2021; 9:749822. [PMID: 34966738 PMCID: PMC8710809 DOI: 10.3389/fcell.2021.749822] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/29/2021] [Indexed: 12/31/2022] Open
Abstract
Premature ovarian failure (POF) has become one of the main causes of infertility in women of childbearing age and the incidence of POF is increasing year by year, seriously affecting the physical and mental health of patients and increasing the economic burden on families and society as a whole. The etiology and pathogenesis of POF are complex and not very clear at present. Currently, hormone replacement therapy is mainly used to improve the symptoms of low estrogen, but cannot fundamentally solve the fertility problem. In recent years, stem cell (SC) transplantation has become one of the research hotspots in the treatment of POF. The results from animal experiments bring hope for the recovery of ovarian function and fertility in patients with POF. In this article, we searched the published literature between 2000 and 2020 from the PubMed database (https://pubmed.ncbi.nlm.nih.gov), and summarized the preclinical research data and possible therapeutic mechanism of mesenchymal stem cells (MSCs) in the treatment of POF. Our aim is to provide useful information for understanding POF and reference for follow-up research and treatment of POF.
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Affiliation(s)
- Jing Wang
- Department of Reproductive Medicine, Department of Prenatal Diagnosis, The First Hospital of Jilin University, Changchun, China
| | - Wanru Liu
- Department of Reproductive Medicine, Department of Prenatal Diagnosis, The First Hospital of Jilin University, Changchun, China
| | - Dehai Yu
- The Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, China
| | - Zongxing Yang
- Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Sijie Li
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xiguang Sun
- Hand Surgery Department, The First Hospital of Jilin University, Changchun, China
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Making More Womb: Clinical Perspectives Supporting the Development and Utilization of Mesenchymal Stem Cell Therapy for Endometrial Regeneration and Infertility. J Pers Med 2021; 11:jpm11121364. [PMID: 34945836 PMCID: PMC8707522 DOI: 10.3390/jpm11121364] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/02/2021] [Accepted: 12/12/2021] [Indexed: 12/12/2022] Open
Abstract
The uterus is a homeostatic organ, unwavering in the setting of monthly endometrial turnover, placental invasion, and parturition. In response to ovarian steroid hormones, the endometrium autologously prepares for embryo implantation and in its absence will shed and regenerate. Dysfunctional endometrial repair and regeneration may present clinically with infertility and abnormal menses. Asherman's syndrome is characterized by intrauterine adhesions and atrophic endometrium, which often impacts fertility. Clinical management of infertility associated with abnormal endometrium represents a significant challenge. Endometrial mesenchymal stem cells (MSC) occupy a perivascular niche and contain regenerative and immunomodulatory properties. Given these characteristics, mesenchymal stem cells of endometrial and non-endometrial origin (bone marrow, adipose, placental) have been investigated for therapeutic purposes. Local administration of human MSC in animal models of endometrial injury reduces collagen deposition, improves angiogenesis, decreases inflammation, and improves fertility. Small clinical studies of autologous MSC administration in infertile women with Asherman's Syndrome suggested their potential to restore endometrial function as evidenced by increased endometrial thickness, decreased adhesions, and fertility. The objective of this review is to highlight translational and clinical studies investigating the use of MSC for endometrial dysfunction and infertility and to summarize the current state of the art in this promising area.
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Mawet M, Perrier d’Hauterive S, Henry L, Potorac I, Kridelka F, Nisolle M, Pintiaux A. Restoration of Fertility in Patients with Spontaneous Premature Ovarian Insufficiency: New Techniques under the Microscope. J Clin Med 2021; 10:jcm10235647. [PMID: 34884349 PMCID: PMC8658421 DOI: 10.3390/jcm10235647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/24/2021] [Accepted: 11/27/2021] [Indexed: 11/16/2022] Open
Abstract
Premature ovarian insufficiency (POI), a condition affecting up to 1% of women by the age of 40 years, is characterized by an extremely low chance of spontaneous pregnancy. Currently, fertility restoration options are virtually nonexistent for this population. To become pregnant, the only solution is egg donation. Interestingly, animal studies have provided encouraging results in terms of fertility restoration, and consequently, research has begun into the most promising approaches for women suffering from POI. The PubMed database was searched for studies in which techniques aiming at restoring fertility in women with spontaneous POI were tested. Although robust studies are lacking, the literature suggests a positive effect of certain techniques on fertility restoration in women with POI. The most promising approaches seem to be intraovarian injection of autologous platelet-rich plasma or of mesenchymal stem cells. In addition to these, in vitro and mechanical activation of dormant follicles and etiology-driven therapies have also been studied with mixed results. No safety concerns were raised in these studies. The absence of robust studies does not allow us to draw meaningful conclusions on the efficacy or superiority of any single technique at this stage, and so research in this area should continue using robust study designs, i.e., multicenter randomized controlled trials including sufficient subjects to achieve statistical power.
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Affiliation(s)
- Marie Mawet
- Service de Gynécologie-Obstétrique, Uliège, Site du CHU, Avenue de l’Hopital 1, 4000 Liège, Belgium; (F.K.); (A.P.)
- Correspondence: ; Tel.: +32-478931670
| | - Sophie Perrier d’Hauterive
- Service de Gynécologie-Obstétrique, Uliège, Site du CHR, Boulevard du 12ème de Ligne, 4000 Liège, Belgium; (S.P.d.); (L.H.); (M.N.)
- GIGA-Stem Cells, Uliège, Site du CHU, Avenue de l’Hopital 1, 4000 Liège, Belgium
| | - Laurie Henry
- Service de Gynécologie-Obstétrique, Uliège, Site du CHR, Boulevard du 12ème de Ligne, 4000 Liège, Belgium; (S.P.d.); (L.H.); (M.N.)
| | - Iulia Potorac
- Service d’Endocrinologie, Uliège, Site du CHU, Avenue de l’Hopital 1, 4000 Liège, Belgium;
| | - Frédéric Kridelka
- Service de Gynécologie-Obstétrique, Uliège, Site du CHU, Avenue de l’Hopital 1, 4000 Liège, Belgium; (F.K.); (A.P.)
| | - Michelle Nisolle
- Service de Gynécologie-Obstétrique, Uliège, Site du CHR, Boulevard du 12ème de Ligne, 4000 Liège, Belgium; (S.P.d.); (L.H.); (M.N.)
| | - Axelle Pintiaux
- Service de Gynécologie-Obstétrique, Uliège, Site du CHU, Avenue de l’Hopital 1, 4000 Liège, Belgium; (F.K.); (A.P.)
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Lin XM, Chen M, Wang QL, Ye XM, Chen HF. Clinical observation of Kuntai capsule combined with Fenmotong in treatment of decline of ovarian reserve function. World J Clin Cases 2021; 9:8349-8357. [PMID: 34754844 PMCID: PMC8554447 DOI: 10.12998/wjcc.v9.i28.8349] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/04/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Decreased ovarian reserve function is an ovarian hypofunction disease that occurs in women before 40 years of age, leading to a decline in fertility and perimenopausal symptoms, such as irregular menstruation, amenorrhea, infertility, decreased libido, and autonomic nervous dysfunction. Fenmatong (FMT) is a compound mixture of estradiol tablets and estradiol didroxyprogesterone tablets, which can improve ovarian reserve function by supplementation of exogenous estrogen. However, this treatment has also been shown to cause breast pain, gastrointestinal discomfort, irregular vaginal bleeding, and changes in sexual desire. In severe cases, FMT can promote the development of breast cancer, endometrial cancer, and venous embolic disease.
AIM To observe the effects of Kuntai capsules and FMT on endocrine indexes and uterine artery blood circulation in patients with decreased ovarian reserve function.
METHODS Patients (130) with decreased ovarian reserve function, who were treated in our hospital from May 2018 to May 2020, were divided into two groups: The FMT group, in which patients were treated with FMT, and the observation group, in which patients were treated with Kuntai capsules. Chinese medicine symptom scores, uterine artery blood flow parameters, ovarian ultrasound test indexes, pictorial blood loss assessment chart (PBAC) scores, and hormone levels were recorded, and total effective rates were calculated for both groups.
RESULTS The total effective rate in the observation group was higher than that in the FMT group (P < 0.05).After treatment, primary symptoms, including low menstrual volume, delayed menstruation, red color and thick consistency of menses, dizziness, palpitation, weakness at the waist and knee, insomnia and excessive dreaming, irritability, and dryness and astringency of the pudendal canal in the observation group decreased, and scores for primary and secondary symptoms in the observation group were significantly lower than those in the FMT group (P < 0.05).The systolic peak flow rate (PSV), end-diastolic flow rate (EDV), ovarian diameter, sinus follicle count, and resistance index (RI) of the uterine arteries in the observation group and FMT group increased after treatment. Notably, the PSV, EDV, ovarian diameter, and antral follicle count in the observation group were higher than those in the FMT group, whereas the RI in the observation group was lower than that in the FMT group (P < 0.05).The PBAC scores in the observation and FMT groups increased after treatment, with that in the observation group becoming significantly higher than that in the FMT group (P < 0.05). After treatment, estradiol (E2) and anti-Mullerian hormone (AMH) levels increased, whereas follicle-stimulating hormone (FSH) levels decreased in the observation group and FMT group; E2 and AMH levels became significantly higher and FSH levels became significantly lower in the observation group than in the FMT group (P < 0.05).
CONCLUSION Compared with FMT, Kuntai capsules promoted uterine artery blood circulation, improved menstruation, relieved symptoms, regulated endocrine function, and improved curative effects.
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Affiliation(s)
- Xin-Miao Lin
- Department of Reproductive Health and Infertility, Zhanjiang Central People’s Hospital, Zhanjiang 524037, Guangdong Province, China
| | - Miao Chen
- Department of Reproductive Health and Infertility, Zhanjiang Central People’s Hospital, Zhanjiang 524037, Guangdong Province, China
| | - Qiao-Ling Wang
- Department of Reproductive Health and Infertility, Zhanjiang Central People’s Hospital, Zhanjiang 524037, Guangdong Province, China
| | - Xiao-Min Ye
- Department of Reproductive Health and Infertility, Zhanjiang Central People’s Hospital, Zhanjiang 524037, Guangdong Province, China
| | - Hao-Fan Chen
- Department of Reproductive Health and Infertility, Zhanjiang Central People’s Hospital, Zhanjiang 524037, Guangdong Province, China
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Tang H, Liu Y, Fan Y, Li C. Therapeutic Effects of Low-Intensity Pulsed Ultrasound on Premature Ovarian Insufficiency. ULTRASOUND IN MEDICINE & BIOLOGY 2021; 47:2377-2387. [PMID: 34088530 DOI: 10.1016/j.ultrasmedbio.2021.04.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 02/20/2021] [Accepted: 04/20/2021] [Indexed: 06/12/2023]
Abstract
We explored the therapeutic effects of low-intensity pulsed ultrasound (LIPUS) on a rat model of ovarian damage induced by cyclophosphamide. A total of 44 female rats with premature ovarian insufficiency induced by cyclophosphamide were randomly divided into two groups (an ultrasound group and a control group); 22 normal rats without premature ovarian insufficiency were also included as a third group. The ultrasound group was treated with LIPUS, while the other two groups received the same treatment but without any power output. We monitored the estrous cycles of all rats. Seven days after treatment, 21 rats were selected to mate with male rats. We then recorded the pregnancy rate along with the number and weight of newborn rats per nest. We collected samples of blood, uterus and ovaries from the remaining 45 rats before they were sacrificed. Compared with the normal group, the control group exhibited disordered estrous cycles, more atretic follicles (p < 0.01), higher levels of serum follicle-stimulating hormone (p < 0.01), fewer other follicles (p < 0.01) and lower serum levels of E2 and anti-Müllerian hormone (p < 0.01). Compared with the control group, the ultrasound group had normal estrous cycles with fewer atretic follicles (p < 0.01), lower levels of serum follicle-stimulating hormone (p < 0.01), more other follicles (p < 0.01) and higher levels of serum E2 (p < 0.01). No significant difference in the levels of serum anti-Müllerian hormone was noted between the control group and the ultrasound group. No significant differences were observed between the three groups with respect to pregnancy rate or the number and weight of newborns per nest (p > 0.05). In conclusion, our data indicate that LIPUS could improve some ovarian functions of rats with premature ovarian insufficiency.
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Affiliation(s)
- Huajun Tang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Yao Liu
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Yijin Fan
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Chengzhi Li
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China.
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Saha S, Roy P, Corbitt C, Kakar SS. Application of Stem Cell Therapy for Infertility. Cells 2021; 10:1613. [PMID: 34203240 PMCID: PMC8303590 DOI: 10.3390/cells10071613] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
Infertility creates an immense impact on the psychosocial wellbeing of affected couples, leading to poor quality of life. Infertility is now considered to be a global health issue affecting approximately 15% of couples worldwide. It may arise from factors related to the male (30%), including varicocele, undescended testes, testicular cancer, and azoospermia; the female (30%), including premature ovarian failure and uterine disorders; or both partners (30%). With the recent advancement in assisted reproduction technology (ART), many affected couples (80%) could find a solution. However, a substantial number of couples cannot conceive even after ART. Stem cells are now increasingly being investigated as promising alternative therapeutics in translational research of regenerative medicine. Tremendous headway has been made to understand the biology and function of stem cells. Considering the minimum ethical concern and easily available abundant resources, extensive research is being conducted on induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSC) for their potential application in reproductive medicine, especially in cases of infertility resulting from azoospermia and premature ovarian insufficiency. However, most of these investigations have been carried out in animal models. Evolutionary divergence observed in pluripotency among animals and humans requires caution when extrapolating the data obtained from murine models to safely apply them to clinical applications in humans. Hence, more clinical trials based on larger populations need to be carried out to investigate the relevance of stem cell therapy, including its safety and efficacy, in translational infertility medicine.
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Affiliation(s)
- Sarama Saha
- Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh 249203, India;
| | - Partha Roy
- Department of Biotechnology, Indian Institute of Technology, Roorkee 247667, India;
| | - Cynthia Corbitt
- Department of Biology, University of Louisville, Louisville, KY 40292, USA;
| | - Sham S. Kakar
- Department of Physiology and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40292, USA
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Jiao Z, Bukulmez O. Potential roles of experimental reproductive technologies in infertile women with diminished ovarian reserve. J Assist Reprod Genet 2021; 38:2507-2517. [PMID: 34100154 DOI: 10.1007/s10815-021-02246-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 05/25/2021] [Indexed: 12/24/2022] Open
Abstract
In assisted reproductive technology treatment, diminished ovarian reserve (DOR) is a condition of utmost clinical and scientific relevance because of its negative influence on patient outcomes. The current methods of infertility treatment may be unsuitable for many women with DOR, which support the need for development of additional approaches to achieve fertility restoration. Various techniques have been tried to improve the quality and increase the quantity of oocytes in DOR patients, including mitochondrial transfer, activation of primordial follicles, in vitro culture of follicles, and regeneration of oocytes from various stem cells. Herein, we review the science behind these experimental reproductive technologies and their potential use to date in clinical studies for infertility treatment in women with DOR.
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Affiliation(s)
- Zexu Jiao
- Division of Reproductive Endocrinology and Infertility, Fertility and Advanced Reproductive Medicine Assisted Reproductive Technologies Program, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Orhan Bukulmez
- Division of Reproductive Endocrinology and Infertility, Fertility and Advanced Reproductive Medicine Assisted Reproductive Technologies Program, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Human Mesenchymal Stem Cell Therapy and Other Novel Treatment Approaches for Premature Ovarian Insufficiency. Reprod Sci 2021; 28:1688-1696. [PMID: 33956339 PMCID: PMC8144118 DOI: 10.1007/s43032-021-00528-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 03/01/2021] [Indexed: 12/11/2022]
Abstract
Premature ovarian insufficiency (POI) is a condition characterized by amenorrhea, hypergonadotropic hypogonadism, estrogen deficiency, and reduced follicle counts leading to infertility under the age of 40. POI occurs in approximately 1-3% of women in the general population. Evaluation is warranted when the diagnosis of POI is made to rule out underlying etiologies, which could be multifactorial. This review serves to cover the novel treatment approaches reported in the literature.
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