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Bashiri Z, Hosseini SJ, Salem M, Koruji M. In vivo and in vitro sperm production: an overview of the challenges and advances in male fertility restoration. Clin Exp Reprod Med 2024; 51:171-180. [PMID: 38525520 PMCID: PMC11372308 DOI: 10.5653/cerm.2023.06569] [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: 10/03/2023] [Accepted: 12/14/2023] [Indexed: 03/26/2024] Open
Abstract
Male infertility can be caused by genetic anomalies, endocrine disorders, inflammation, and exposure to toxic chemicals or gonadotoxic treatments. Therefore, several recent studies have concentrated on the preservation and restoration of fertility to enhance the quality of life for affected individuals. It is currently recommended to biobank the tissue extracted from testicular biopsies to provide a later source of spermatogonial stem cells (SSCs). Another successful approach has been the in vitro production of haploid male germ cells. The capacity of SSCs to transform into sperm, as in testicular tissue transplantation, SSC therapy, and in vitro or ex vivo spermatogenesis, makes them ideal candidates for in vivo fertility restoration. The transplantation of SSCs or testicular tissue to regenerate spermatogenesis and create embryos has been achieved in nonhuman mammal species. Although the outcomes of human trials have yet to be released, this method may soon be approved for clinical use in humans. Furthermore, regenerative medicine techniques that develop tissue or cells on organic or synthetic scaffolds enriched with bioactive molecules have also gained traction. All of these methods are now in different stages of experimentation and clinical trials. However, thanks to rigorous studies on the safety and effectiveness of SSC-based reproductive treatments, some of these techniques may be clinically available in upcoming decades.
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Affiliation(s)
- Zahra Bashiri
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Omid Fertility and Infertility Clinic, Hamedan, Iran
| | - Seyed Jamal Hosseini
- Biomedical Engineering Department, Amirkabir University of Technology, Tehran, Iran
- Department of Pharmaceutical Biomaterials and Medical Biomaterials Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Salem
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Koruji
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
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Mohammadi A, Shabani R, Bashiri Z, Rafiei S, Asgari H, Koruji M. Therapeutic potential of exosomes in spermatogenesis regulation and male infertility. Biol Cell 2024; 116:e2300127. [PMID: 38593304 DOI: 10.1111/boc.202300127] [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: 01/21/2024] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Spermatogenesis is a fundamental process crucial for male reproductive health and fertility. Exosomes, small membranous vesicles released by various cell types, have recently garnered attention for their role in intercellular communication. OBJECTIVE This review aims to comprehensively explore the role of exosomes in regulating spermatogenesis, focusing on their involvement in testicular development and cell-to-cell communication. METHODS A systematic examination of literature was conducted to gather relevant studies elucidating the biogenesis, composition, and functions of exosomes in the context of spermatogenesis. RESULTS Exosomes play a pivotal role in orchestrating the complex signaling networks required for proper spermatogenesis. They facilitate the transfer of key regulatory molecules between different cell populations within the testes, including Sertoli cells, Leydig cells, and germ cells. CONCLUSION The emerging understanding of exosome-mediated communication sheds light on novel mechanisms underlying spermatogenesis regulation. Further research in this area holds promise for insights into male reproductive health and potential therapeutic interventions.
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Affiliation(s)
- Amirhossein Mohammadi
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ronak Shabani
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Reproductive Sciences and Technology Research Center, Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Bashiri
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Omid Fertility & Infertility Clinic, Hamedan, Iran
| | - Sara Rafiei
- Department of Botany and Plant Sciences, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Hamidreza Asgari
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Morteza Koruji
- Stem Cell and Regenerative Medicine Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Parivesh A, Délot E, Reyes A, Ryan J, Bhattacharya S, Harley V, Vilain E. Reprograming skin fibroblasts into Sertoli cells: a patient-specific tool to understand effects of genetic variants on gonadal development. Biol Sex Differ 2024; 15:24. [PMID: 38520033 PMCID: PMC10958866 DOI: 10.1186/s13293-024-00599-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 02/22/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Disorders/differences of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. With overlapping phenotypes and multiple genes involved, poor diagnostic yields are achieved for many of these conditions. The current DSD diagnostic regimen can be augmented by investigating transcriptome/proteome in vivo, but it is hampered by the unavailability of affected gonadal tissue at the relevant developmental stage. We try to mitigate this limitation by reprogramming readily available skin tissue-derived dermal fibroblasts into Sertoli cells (SC), which could then be deployed for different diagnostic strategies. SCs form the target cell type of choice because they act like an organizing center of embryonic gonadal development and many DSD arise when these developmental processes go awry. METHODS We employed a computational predictive algorithm for cell conversions called Mogrify to predict the transcription factors (TFs) required for direct reprogramming of human dermal fibroblasts into SCs. We established trans-differentiation culture conditions where stable transgenic expression of these TFs was achieved in 46, XY adult dermal fibroblasts using lentiviral vectors. The resulting Sertoli like cells (SLCs) were validated for SC phenotype using several approaches. RESULTS SLCs exhibited Sertoli-like morphological and cellular properties as revealed by morphometry and xCelligence cell behavior assays. They also showed Sertoli-specific expression of molecular markers such as SOX9, PTGDS, BMP4, or DMRT1 as revealed by IF imaging, RNAseq and qPCR. The SLC transcriptome shared about two thirds of its differentially expressed genes with a human adult SC transcriptome and expressed markers typical of embryonic SCs. Notably, SLCs lacked expression of most markers of other gonadal cell types such as Leydig, germ, peritubular myoid or granulosa cells. CONCLUSIONS The trans-differentiation method was applied to a variety of commercially available 46, XY fibroblasts derived from patients with DSD and to a 46, XX cell line. The DSD SLCs displayed altered levels of trans-differentiation in comparison to normal 46, XY-derived SLCs, thus showcasing the robustness of this new trans-differentiation model. Future applications could include using the SLCs to improve definitive diagnosis of DSD in patients with variants of unknown significance.
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Affiliation(s)
- Abhinav Parivesh
- Center for Genetic Medicine Research, Children's National Hospital, Washington D.C., 20010, USA
| | - Emmanuèle Délot
- Center for Genetic Medicine Research, Children's National Hospital, Washington D.C., 20010, USA
| | - Alejandra Reyes
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, 3168, Australia
| | - Janelle Ryan
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, 3168, Australia
| | - Surajit Bhattacharya
- Center for Genetic Medicine Research, Children's National Hospital, Washington D.C., 20010, USA
| | - Vincent Harley
- Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, 3168, Australia
| | - Eric Vilain
- Institute for Clinical and Translational Science, University of California, Irvine, CA, USA.
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Mo P, Zhao Z, Ke X, Fan Y, Li C. Effects of clinical medications on male fertility and prospects for stem cell therapy. Front Cell Dev Biol 2023; 11:1258574. [PMID: 37791073 PMCID: PMC10543686 DOI: 10.3389/fcell.2023.1258574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 09/07/2023] [Indexed: 10/05/2023] Open
Abstract
An increasing number of men require long-term drug therapy for various diseases. However, the effects of long-term drug therapy on male fertility are often not well evaluated in clinical practice. Meanwhile, the development of stem cell therapy and exosomes treatment methods may provide a new sight on treating male infertility. This article reviews the influence and mechanism of small molecule medications on male fertility, as well as progress of stem cell and exosomes therapy for male infertility with the purpose on providing suggestions (recommendations) for evaluating the effect of drugs on male fertility (both positive and negative effect on male fertility) in clinical application and providing strategies for diagnosis and treatment of male infertility.
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Affiliation(s)
| | | | | | - Yong Fan
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Department of Obstetrics and Gynecology, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Chaohui Li
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, Department of Obstetrics and Gynecology, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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Rosner M, Horer S, Feichtinger M, Hengstschläger M. Multipotent fetal stem cells in reproductive biology research. Stem Cell Res Ther 2023; 14:157. [PMID: 37287077 DOI: 10.1186/s13287-023-03379-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023] Open
Abstract
Due to the limited accessibility of the in vivo situation, the scarcity of the human tissue, legal constraints, and ethical considerations, the underlying molecular mechanisms of disorders, such as preeclampsia, the pathological consequences of fetomaternal microchimerism, or infertility, are still not fully understood. And although substantial progress has already been made, the therapeutic strategies for reproductive system diseases are still facing limitations. In the recent years, it became more and more evident that stem cells are powerful tools for basic research in human reproduction and stem cell-based approaches moved into the center of endeavors to establish new clinical concepts. Multipotent fetal stem cells derived from the amniotic fluid, amniotic membrane, chorion leave, Wharton´s jelly, or placenta came to the fore because they are easy to acquire, are not associated with ethical concerns or covered by strict legal restrictions, and can be banked for autologous utilization later in life. Compared to adult stem cells, they exhibit a significantly higher differentiation potential and are much easier to propagate in vitro. Compared to pluripotent stem cells, they harbor less mutations, are not tumorigenic, and exhibit low immunogenicity. Studies on multipotent fetal stem cells can be invaluable to gain knowledge on the development of dysfunctional fetal cell types, to characterize the fetal stem cells migrating into the body of a pregnant woman in the context of fetomaternal microchimerism, and to obtain a more comprehensive picture of germ cell development in the course of in vitro differentiation experiments. The in vivo transplantation of fetal stem cells or their paracrine factors can mediate therapeutic effects in preeclampsia and can restore reproductive organ functions. Together with the use of fetal stem cell-derived gametes, such strategies could once help individuals, who do not develop functional gametes, to conceive genetically related children. Although there is still a long way to go, these developments regarding the usage of multipotent fetal stem cells in the clinic should continuously be accompanied by a wide and detailed ethical discussion.
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Affiliation(s)
- Margit Rosner
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | - Stefanie Horer
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria
| | | | - Markus Hengstschläger
- Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria.
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Zhang J, Wei L, Deng X, Luo C, Zhu Q, Lu S, Mao C. Current status and reflections on fertility preservation in China. J Assist Reprod Genet 2022; 39:2835-2845. [PMID: 36322229 PMCID: PMC9790826 DOI: 10.1007/s10815-022-02648-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/20/2022] [Indexed: 11/07/2022] Open
Abstract
PURPOSE With the progress of medical technology and renovated conception of fertility, the prospective studies and practice of fertility preservation are drawing more and more attention from medical workers. With the largest population of over 1.4 billion, China makes the experience accumulated in fertility preservation efforts even more relevant. This article summarizes China's experience and shares it with the world to promote the healthy development of fertility preservation. METHODS This study was based on multiple Chinese expert consensuses on fertility preservation issued in 2021 and the current national regulations and principles, compared with the latest advice and guidelines issued by global reproductive authorities such as the ASRM and ESHRE. Summarize the experience and reflection of Chinese scholars in the process of fertility preservation. RESULTS This study reports on the current situation of fertility preservation in China, sharing the Chinese experience gained in the process of development, and offering Chinese reflections on worrying issues. CONCLUSION Fertility preservation is a medical and social issue of reproductive health security, which is conducive to the sound development of the world population and social production.
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Affiliation(s)
- Jiakai Zhang
- Reproductive Medicine Center, First Affiliated Hospital of Soochow University, 899 Pinghai Rd, Suzhou Suzhou, Jiangsu, 215000 China
- Marxism Research Institute, Soochow University, Suzhou, Jiangsu, 215123 China
- Suzhou High School Affiliated to Xi’an Jiaotong University, Suzhou, Jiangsu, 215000 China
| | - Lun Wei
- Reproductive Medicine Center, First Affiliated Hospital of Soochow University, 899 Pinghai Rd, Suzhou Suzhou, Jiangsu, 215000 China
| | - Xiaoling Deng
- Reproductive Medicine Center, First Affiliated Hospital of Soochow University, 899 Pinghai Rd, Suzhou Suzhou, Jiangsu, 215000 China
| | - Chao Luo
- Reproductive Medicine Center, First Affiliated Hospital of Soochow University, 899 Pinghai Rd, Suzhou Suzhou, Jiangsu, 215000 China
| | - Qianmeng Zhu
- Reproductive Medicine Center, First Affiliated Hospital of Soochow University, 899 Pinghai Rd, Suzhou Suzhou, Jiangsu, 215000 China
| | - Shucheng Lu
- Marxism Research Institute, Soochow University, Suzhou, Jiangsu, 215123 China
| | - Caiping Mao
- Reproductive Medicine Center, First Affiliated Hospital of Soochow University, 899 Pinghai Rd, Suzhou Suzhou, Jiangsu, 215000 China
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Hosseini H, DeBenedetto C, Eleswarapu SV, Ng G, Sturm RM. De novo testicular tissue generation from non-testicular cell lines, biologic and synthetic scaffolds: Current findings and future translational applications. Front Cell Dev Biol 2022; 10:954196. [PMID: 36407104 PMCID: PMC9667054 DOI: 10.3389/fcell.2022.954196] [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: 05/27/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022] Open
Abstract
In recent decades, reproductive science has revolutionized the options for biological parenthood for the 20-50% of infertility cases affected by male factors. However, current solutions exclude those who are infertile due to absent testicular tissue. This includes anorchic 46, XY individuals due to trauma or congenital factors and transgender men with a 46, XX genotype. There is a clinical need for methods to restore testicular function independent of pre-existing testicular tissue. This mini-review analyzes studies that have applied non-testicular cell lines to generate germline and non-germline testicular parenchymal components. While only 46, XY cell lines have been evaluated in this context to date, the potential for future application of cell lines from 46, XX individuals is also included. Additionally, the role of varied culture methods, media supplementation, and biologic and synthetic scaffolds to further support testicular parenchyma generation are critiqued. De novo testicular tissue generation in this manner will require a focus on both cellular and environmental aspects of tissue engineering. Put together, these studies highlight the future potential for expanded clinical, reproductive, and endocrine management options for individuals who are currently excluded from aspects of biologic reproduction most consistent with their gender identity and reproductive preferences.
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Affiliation(s)
- Helia Hosseini
- Department of Bioengineering, Los Angeles, CA, United States
| | | | | | - Gladys Ng
- Department of Urology, Los Angeles, CA, United States
| | - Renea M. Sturm
- Department of Urology, Los Angeles, CA, United States,UCLA Mattel Children's Hospital, Los Angeles, CA, United States,*Correspondence: Renea M. Sturm,
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8
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Jorgensen A, Svingen T, Miles H, Chetty T, Stukenborg JB, Mitchell RT. Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models. Horm Res Paediatr 2021; 96:190-206. [PMID: 34607330 DOI: 10.1159/000519964] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/11/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. SUMMARY In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. KEY MESSAGES Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.
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Affiliation(s)
- Anne Jorgensen
- Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark
| | - Terje Svingen
- Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Harriet Miles
- Royal Hospital for Children and Young People, Edinburgh, UK
| | - Tarini Chetty
- Royal Hospital for Children and Young People, Edinburgh, UK
| | - Jan-Bernd Stukenborg
- NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Rod T Mitchell
- Royal Hospital for Children and Young People, Edinburgh, UK
- MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK
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Rahmani-Moghadam E, Zarrin V, Mahmoodzadeh A, Owrang M, Talaei-Khozani T. Comparison of the Characteristics of Breast Milk-derived Stem Cells with the Stem Cells Derived from the Other Sources: A Comparative Review. Curr Stem Cell Res Ther 2021; 17:71-90. [PMID: 34161214 DOI: 10.2174/1574888x16666210622125309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/14/2021] [Accepted: 03/28/2021] [Indexed: 11/22/2022]
Abstract
Breast milk (BrM) not only supplies nutrition, but it also contains a diverse population of cells. It has been estimated that up to 6% of the cells in human milk possess the characteristics of mesenchymal stem cells (MSC). Available data also indicate that these cells are multipotent and capable of self-renewal and differentiation with other cells. In this review, we have compared different characteristics, such as CD markers, differentiation capacity, and morphology of stem cells, derived from human breast milk (hBr-MSC) with human bone marrow (hBMSC), Wharton's jelly (WJMSC), and human adipose tissue (hADMSC). Through the literature review, it was revealed that human breast milk-derived stem cells specifically express a group of cell surface markers, including CD14, CD31, CD45, and CD86. Importantly, a group of markers, CD13, CD29, CD44, CD105, CD106, CD146, and CD166, were identified, which were common in the four sources of stem cells. WJMSC, hBMSC, hADMSC, and hBr-MSC are potently able to differentiate into the mesoderm, ectoderm, and endoderm cell lineages. The ability of hBr-MSCs todifferentiate into the neural stem cells, neurons, adipocyte, hepatocyte, chondrocyte, osteocyte, and cardiomyocytes has made these cells a promising source of stem cells in regenerative medicine, while isolation of stem cells from the commonly used sources, such as bone marrow, requires invasive procedures. Although autologous breast milk-derived stem cells are an accessible source for women who are in the lactation period, breast milk can be considered as a source of stem cells with high differentiation potential without any ethical concern.
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Affiliation(s)
- Ebrahim Rahmani-Moghadam
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahideh Zarrin
- Laboratory for Stem Cell Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Mahmoodzadeh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Marzieh Owrang
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Pediatric and Adolescent Oncofertility in Male Patients-From Alpha to Omega. Genes (Basel) 2021; 12:genes12050701. [PMID: 34066795 PMCID: PMC8150386 DOI: 10.3390/genes12050701] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/02/2021] [Accepted: 05/04/2021] [Indexed: 01/15/2023] Open
Abstract
This article reviews the latest information about preserving reproductive potential that can offer enhanced prospects for future conception in the pediatric male population with cancer, whose fertility is threatened because of the gonadotoxic effects of chemotherapy and radiation. An estimated 400,000 children and adolescents aged 0–19 years will be diagnosed with cancer each year. Fertility is compromised in one-third of adult male survivors of childhood cancer. We present the latest approaches and techniques for fertility preservation, starting with fertility preservation counselling, a clinical practice guideline used around the world and finishing with recent advances in basic science and translational research. Improving strategies for the maturation of germ cells in vitro combined with new molecular techniques for gene editing could be the next scientific keystone to eradicate genetic diseases such as cancer related mutations in the offspring of cancer survivors.
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Mashiach J, Zohni K, Lopez L, Filice M, Garcia M, Wyse B, Glass K, Dviri M, Baram S, Gauthier-Fisher A, Librach CL. Human umbilical cord perivascular cells prevent chemotherapeutic drug-induced male infertility in a mouse model. F&S SCIENCE 2021; 2:24-32. [PMID: 35559762 DOI: 10.1016/j.xfss.2020.12.002] [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: 09/14/2020] [Revised: 11/13/2020] [Accepted: 12/03/2020] [Indexed: 06/15/2023]
Abstract
OBJECTIVE To study whether intratesticular (IT) administration of 2 sources of human umbilical cord perivascular cells (HUCPVC), rich and potent sources of mesenchymal stromal cells (MSC), before chemotherapy can prevent infertility in a mouse model. DESIGN Two control groups of CD1 male mice without busulfan (BUS) administration (untreated and IT media injection groups) were included. Experimental groups included IT administration of media, first trimester (FTM) HUCPVCs or term HUCPVCs (n = 5 each) injected 3 days before BUS treatment (20 mg/kg). All groups were included in a mating time course study over 6 months. SETTING Preclinical study in a fertility center research laboratory. PATIENTS Not applicable. INTERVENTION IT delivery of FTM or term HUCPVC before BUS treatment. MAIN OUTCOME MEASURES Pregnancies, litter sizes, and gross morphology of offspring were monitored. Caudal epididymal sperm concentration, motility, and progressive motility were assessed by computer-assisted sperm analysis. Spermatogenesis was also assessed histologically in testicular tissue sections. RESULTS FTM and term HUCPVC displayed an MSC-associated immunophenotype and expressed transcripts encoding paracrine factors known to regulate the testicular cell niche. IT administration of FTM and term HUCPVC before chemotherapy promoted the recovery of spermatogenesis and fertility compared with BUS-treated animals that received a media injection. Although the total number of pups sired over 6 months by males treated with FTM or term HUCPVC was reduced compared with untreated or media-injected controls, litter size and sperm parameters in fertile animals did not differ between control and cell-treated groups. CONCLUSION HUCPVC represent a promising source of MSC-based therapy to prevent gonadotoxic chemotherapeutic drug-induced infertility.
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Affiliation(s)
| | - Khaled Zohni
- CReATe Fertility Centre, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada; Department of Obstetrics and Gynecology, University of Manitoba, Winnipeg, Manitoba, Canada; Heartland Fertility and Gynecology clinic, Winnipeg, Manitoba, Canada
| | | | | | | | | | - Karen Glass
- CReATe Fertility Centre, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada
| | - Michal Dviri
- CReATe Fertility Centre, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada
| | - Shira Baram
- CReATe Fertility Centre, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada; Emek Medical Center, Afula, Israel
| | | | - Clifford L Librach
- CReATe Fertility Centre, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada; Department of Physiology University of Toronto, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada; Department of Gynecology, Women's College Hospital, Toronto, Canada
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12
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Zohni K, Lopez L, Mander P, Szaraz P, Filice M, Wyse BA, Garcia M, Gat I, Glass K, Gauthier-Fisher A, Librach CL. Human umbilical cord perivascular cells maintain regenerative traits following exposure to cyclophosphamide. Cancer Lett 2020; 501:133-146. [PMID: 33387641 DOI: 10.1016/j.canlet.2020.12.035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/15/2020] [Accepted: 12/21/2020] [Indexed: 11/19/2022]
Abstract
Chemotherapies can cause germ cell depletion and gonadal failure. When injected post-chemotherapy, mesenchymal stromal cells (MSCs) from various sources have been shown to have regenerative effects in rodent models of chemotherapy-induced gonadal injury. Here, we evaluated two properties of a novel source of MSC, first trimester (FTM) human umbilical cord perivascular cells (HUCPVCs) (with increased regenerative potential compared to older sources), that may render them a promising candidate for chemotherapeutic gonadal injury prevention. Firstly, their ability to resist the cytotoxic effects of cyclophosphamide (CTX) in vitro, as compared to term HUCPVCs and bone marrow cells (BMSCs); and secondly, whether they prevent gonadal dysfunction if delivered prior to gonadotoxic therapy in vivo. BMSC, FTM HUCPVC, term HUCPVC, and control NTERA2 cells were treated with moderate (150 μmol/L) and high (300 μmol/L) doses of CTX in vitro. Viability, proliferative capacity, mesenchymal cell lineage markers and differentiation capacity, immunogenicity, and paracrine gene expression were assessed. CTX was administered to Wistar rats 2 days following an intra-ovarian injection of FTM HUCPVC. HUCPVC survival and ovarian follicle numbers were assessed using histological methods. We conclude that FTM HUCPVC maintain key regenerative properties following chemotherapy exposure and that pre-treatment with these cells may prevent CTX-induced ovarian damage in vivo. Therefore, HUCPVCs are promising candidates for fertility preservation.
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Affiliation(s)
- Khaled Zohni
- CReATe Fertility Centre, Toronto, Ontario, Canada; Department of Obstetrics & Gynecology, University of Toronto, Toronto, Canada; Department of Obstetrics and Gynecology, University of Manitoba, Winnipeg, Canada; Heartland Fertility and Gynecology Clinic, Winnipeg, Manitoba, Canada
| | - Lianet Lopez
- CReATe Fertility Centre, Toronto, Ontario, Canada
| | | | - Peter Szaraz
- CReATe Fertility Centre, Toronto, Ontario, Canada
| | | | | | | | - Itai Gat
- CReATe Fertility Centre, Toronto, Ontario, Canada; Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel HaShomer, Ramat Gan, Affiliated to Sackler Medical School, University of Tel Aviv, Israel
| | - Karen Glass
- CReATe Fertility Centre, Toronto, Ontario, Canada; Department of Obstetrics & Gynecology, University of Toronto, Toronto, Canada
| | | | - Clifford L Librach
- CReATe Fertility Centre, Toronto, Ontario, Canada; Department of Obstetrics & Gynecology, University of Toronto, Toronto, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Department of Gynecology, Women's College Hospital, Toronto, ON, Canada.
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13
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An In Vitro Differentiation Protocol for Human Embryonic Bipotential Gonad and Testis Cell Development. Stem Cell Reports 2020; 15:1377-1391. [PMID: 33217324 PMCID: PMC7724470 DOI: 10.1016/j.stemcr.2020.10.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 10/21/2020] [Accepted: 10/21/2020] [Indexed: 01/12/2023] Open
Abstract
Currently an in vitro model that fully recapitulates the human embryonic gonad is lacking. Here we describe a fully defined feeder-free protocol to generate early testis-like cells with the ability to be cultured as an organoid, from human induced pluripotent stem cells. This stepwise approach uses small molecules to mimic embryonic development, with upregulation of bipotential gonad markers (LHX9, EMX2, GATA4, and WT1) at day 10 of culture, followed by induction of testis Sertoli cell markers (SOX9, WT1, and AMH) by day 15. Aggregation into 3D structures and extended culture on Transwell filters yielded organoids with defined tissue structures and distinct Sertoli cell marker expression. These studies provide insight into human gonadal development, suggesting that a population of precursor cells may originate from a more lateral region of the mesoderm. Our protocol represents a significant advance toward generating a much-needed human gonad organoid for studying disorders/differences of sex development.
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14
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Liu HC, Xie Y, Deng CH, Liu GH. Stem cell-based therapies for fertility preservation in males: Current status and future prospects. World J Stem Cells 2020; 12:1097-1112. [PMID: 33178394 PMCID: PMC7596443 DOI: 10.4252/wjsc.v12.i10.1097] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/13/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
With the decline in male fertility in recent years, strategies for male fertility preservation have received increasing attention. In this study, by reviewing current treatments and recent publications, we describe research progress in and the future directions of stem cell-based therapies for male fertility preservation, focusing on the use of spermatogonial stem cells (SSCs), SSC niches, SSC-based testicular organoids, other stem cell types such as mesenchymal stem cells, and stem cell-derived extracellular vesicles. In conclusion, a more comprehensive understanding of the germ cell microenvironment, stem cell-derived extracellular vesicles, and testicular organoids will play an important role in achieving male fertility preservation.
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Affiliation(s)
- Han-Chao Liu
- Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Yun Xie
- Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Chun-Hua Deng
- Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Gui-Hua Liu
- Reproductive Medicine Research Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, Guangdong Province, China
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15
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Bishop TF, Van Eenennaam AL. Genome editing approaches to augment livestock breeding programs. ACTA ACUST UNITED AC 2020; 223:223/Suppl_1/jeb207159. [PMID: 32034040 DOI: 10.1242/jeb.207159] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The prospect of genome editing offers a number of promising opportunities for livestock breeders. Firstly, these tools can be used in functional genomics to elucidate gene function, and identify causal variants underlying monogenic traits. Secondly, they can be used to precisely introduce useful genetic variation into structured livestock breeding programs. Such variation may include repair of genetic defects, the inactivation of undesired genes, and the moving of useful alleles and haplotypes between breeds in the absence of linkage drag. Editing could also be used to accelerate the rate of genetic progress by enabling the replacement of the germ cell lineage of commercial breeding animals with cells derived from genetically elite lines. In the future, editing may also provide a useful complement to evolving approaches to decrease the length of the generation interval through in vitro generation of gametes. For editing to be adopted, it will need to seamlessly integrate with livestock breeding schemes. This will likely involve introducing edits into multiple elite animals to avoid genetic bottlenecks. It will also require editing of different breeds and lines to maintain genetic diversity, and enable structured cross-breeding. This requirement is at odds with the process-based trigger and event-based regulatory approach that has been proposed for the products of genome editing by several countries. In the absence of regulatory harmony, researchers in some countries will have the ability to use genome editing in food animals, while others will not, resulting in disparate access to these tools, and ultimately the potential for global trade disruptions.
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16
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Barretto TA, Park K, Maghen L, Park E, Kenigsberg S, Gallagher D, Liu E, Gauthier-Fisher A, Librach C, Baker A. Axon Degeneration Is Rescued with Human Umbilical Cord Perivascular Cells: A Potential Candidate for Neuroprotection After Traumatic Brain Injury. Stem Cells Dev 2019; 29:198-211. [PMID: 31701812 DOI: 10.1089/scd.2019.0135] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Traumatic brain injury (TBI) leads to delayed secondary injury events consisting of cellular and molecular cascades that exacerbate the initial injury. Human umbilical cord perivascular cells (HUCPVCs) secrete neurotrophic and prosurvival factors. In this study, we examined the effects of HUCPVC in sympathetic axon and cortical axon survival models and sought to determine whether HUCPVC provide axonal survival cues. We then examined the effects of the HUCPVC in an in vivo fluid percussion injury model of TBI. Our data indicate that HUCPVCs express neurotrophic and neural survival factors. They also express and secrete relevant growth and survival proteins when cultured alone, or in the presence of injured axons. Coculture experiments indicate that HUCPVCs interact preferentially with axons when cocultured with sympathetic neurons and reduce axonal degeneration. Nerve growth factor withdrawal in axonal compartments resulted in 66 ± 3% axon degeneration, whereas HUCPVC coculture rescued axon degeneration to 35 ± 3%. Inhibition of Akt (LY294002) resulted in a significant increase in degeneration compared with HUCPVC cocultures (48 ± 7% degeneration). Under normoxic conditions, control cultures showed 39 ± 5% degeneration. Oxygen glucose deprivation (OGD) resulted in 58 ± 3% degeneration and OGD HUCPVC cocultures reduced degeneration to 34 ± 5% (p < 0.05). In an in vivo model of TBI, immunohistochemical analysis of NF200 showed improved axon morphology in HUCPVC-treated animals compared with injured animals. These data presented in this study indicate an important role for perivascular cells in protecting axons from injury and a potential cell-based therapy to treat secondary injury after TBI.
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Affiliation(s)
- Tanya A Barretto
- Keenan Research Center, St. Michael's Hospital, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Katya Park
- CReATe Fertility Center, Toronto, Canada
| | | | - Eugene Park
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | | | | | - Elaine Liu
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | | | - Clifford Librach
- CReATe Fertility Center, Toronto, Canada.,Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada.,Department of Physiology, University of Toronto, Toronto, Canada.,Division of Reproductive Endocrinology and Infertility, Departments of Obstetrics and Gynecology, Sunnybrook Health Sciences Center and Women's College Hospital, Toronto, Canada
| | - Andrew Baker
- Keenan Research Center, St. Michael's Hospital, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada.,Department of Critical Care, St. Michael's Hospital, Toronto, Canada.,Department of Anesthesia, University of Toronto, Toronto, Canada
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17
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Rodríguez Gutiérrez D, Biason-Lauber A. Pluripotent Cell Models for Gonadal Research. Int J Mol Sci 2019; 20:ijms20215495. [PMID: 31690065 PMCID: PMC6862629 DOI: 10.3390/ijms20215495] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 10/30/2019] [Accepted: 11/01/2019] [Indexed: 12/27/2022] Open
Abstract
Sex development is a complex process involving many genes and hormones. Defects in this process lead to Differences of Sex Development (DSD), a group of heterogeneous conditions not as rare as previously thought. Part of the obstacles in proper management of these patients is due to an incomplete understanding of the genetics programs and molecular pathways involved in sex development and DSD. Several challenges delay progress and the lack of a proper model system for the single patient severely hinders advances in understanding these diseases. The revolutionary techniques of cellular reprogramming and guided in vitro differentiation allow us now to exploit the versatility of induced pluripotent stem cells to create alternatives models for DSD, ideally on a patient-specific personalized basis.
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Affiliation(s)
- Daniel Rodríguez Gutiérrez
- Endocrinology Division, Department of Endocrinology, Metabolism and Cardiovascular System, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland.
| | - Anna Biason-Lauber
- Endocrinology Division, Department of Endocrinology, Metabolism and Cardiovascular System, Section of Medicine, University of Fribourg, 1700 Fribourg, Switzerland.
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18
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Gauthier-Fisher A, Kauffman A, Librach CL. Potential use of stem cells for fertility preservation. Andrology 2019; 8:862-878. [PMID: 31560823 DOI: 10.1111/andr.12713] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/19/2019] [Accepted: 09/23/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Infertility and gonadal dysfunction can result from gonadotoxic therapies, environmental exposures, aging, or genetic conditions. In men, non-obstructive azoospermia (NOA) results from defects in the spermatogenic process that can be attributed to spermatogonial stem cells (SSC) or their niche, or both. While assisted reproductive technologies and sperm banking can enable fertility preservation (FP) in men of reproductive age who are at risk for infertility, FP for pre-pubertal patients remains experimental. Therapeutic options for NOA are limited. The rapid advance of stem cell research and of gene editing technologies could enable new FP options for these patients. Induced pluripotent stem cells (iPSC), SSC, and testicular niche cells, as well as mesenchymal stromal cells (aka medicinal signaling cells, MSCs), have been investigated for their potential use in male FP strategies. OBJECTIVE Here, we review the benefits and challenges for three types of stem cell-based approaches under investigation for male FP, focusing on the role that promising sources of MSC derived from human umbilical cord, specifically human umbilical cord perivascular cells (HUCPVC), could fulfill. These approaches are as follows: 1. isolation and ex vivo expansion of autologous SSC for in vivo transplantation or in vitro spermatogenesis; 2. in vitro differentiation toward germ cell and testicular somatic cell lineages using autologous SSC, or stem cells such iPSC or MSC; and 3. protection or regeneration of the spermatogenic niche after gonadotoxic insults in vivo. CONCLUSION Our studies suggest that HUCPVC are promising sources of cells that could be utilized in multiple aspects of male FP strategies.
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Affiliation(s)
| | - A Kauffman
- CReATe Fertility Centre, Toronto, ON, Canada
| | - C L Librach
- CReATe Fertility Centre, Toronto, ON, Canada.,Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada.,Department of Physiology, University of Toronto, Toronto, ON, Canada.,Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.,Department of Gynecology, Women's College Hospital, University of Toronto, Toronto, ON, Canada
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19
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Szaraz P, Mander P, Gasner N, Librach M, Iqbal F, Librach C. Glucose withdrawal induces Endothelin 1 release with significant angiogenic effect from first trimester (FTM), but not term human umbilical cord perivascular cells (HUCPVC). Angiogenesis 2019; 23:131-144. [PMID: 31576475 DOI: 10.1007/s10456-019-09682-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 09/19/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Perivascular cells (PVC) and their "progeny," mesenchymal stromal cells (MSC), have high therapeutic potential for ischemic diseases. While hypoxia can increase their angiogenic properties, the other aspect of ischemic conditions-glucose shortage-is deleterious for MSC and limits their therapeutic applicability. Regenerative cells in developing vascular tissues, however, can adapt to varying glucose environment and react in a tissue-protective manner. Placental development and fetal insulin production generate different glucose fluxes in early and late extraembryonic tissues. We hypothesized that FTM HUCPVC, which are isolated from a developing vascular tissue with varying glucose availability react to low-glucose conditions in a pro-angiogenic manner in vitro. METHODS Xeno-free (Human Platelet Lysate 2.5%) expanded FTM (n = 3) and term (n = 3) HUCPVC lines were cultured in low (2 mM) and regular (4 mM) glucose conditions. After 72 h, the expression (Next Generation Sequencing) and secretion (Proteome Profiler) of angiogenic factors and the functional angiogenic effect (rat aortic ring assay and Matrigel™ plug) of the conditioned media were quantified and statistically compared between all cultures. RESULTS Low-glucose conditions had a significant post-transcriptional inductive effect on FTM HUCPVC angiogenic factor secretion, resulting in significantly higher VEGFc and Endothelin 1 release in 3 days compared to term counterparts. Conditioned media from low-glucose FTM HUCPVC cultures had a significantly higher endothelial network enhancing effect compared to all other experimental groups both in vitro aortic ring assay and in subcutan Matrigel™ plugs. Endothelin 1 depletion of the low-glucose FTM HUCPVC conditioned media significantly diminished its angiogenic effect CONCLUSIONS: FTM HUCPVC isolated from an early extraembryonic tissue show significant pro-angiogenic paracrine reaction in low-glucose conditions at least in part through the excess release of Endothelin 1. This can be a substantial advantage in cell therapy applications for ischemic injuries.
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Affiliation(s)
- Peter Szaraz
- Research Department, Create Program Inc., Suite 412, Toronto, ON, M5G 1N8, Canada.
| | - Poonam Mander
- Research Department, Create Program Inc., Suite 412, Toronto, ON, M5G 1N8, Canada
| | - Nadav Gasner
- Research Department, Create Program Inc., Suite 412, Toronto, ON, M5G 1N8, Canada
| | - Max Librach
- Research Department, Create Program Inc., Suite 412, Toronto, ON, M5G 1N8, Canada
| | - Farwah Iqbal
- Department Physiology, University of Toronto, Toronto, ON, Canada
| | - Clifford Librach
- Research Department, Create Program Inc., Suite 412, Toronto, ON, M5G 1N8, Canada.,Department Physiology, University of Toronto, Toronto, ON, Canada.,Department Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada
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20
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Eliyasi Dashtaki M, Hemadi M, Saki G, Mohammadiasl J, Khodadadi A. Spermatogenesis Recovery Potentials after Transplantation of Adipose Tissue-Derived Mesenchymal Stem Cells Cultured with Growth Factors in Experimental Azoospermic Mouse Models. CELL JOURNAL 2019; 21:401-409. [PMID: 31376321 PMCID: PMC6722443 DOI: 10.22074/cellj.2020.6055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 11/17/2018] [Indexed: 12/26/2022]
Abstract
Objective Approximately 1% of the male population suffers from obstructive or non-obstructive azoospermia. Previous
in vitro studies have successfully differentiated mesenchymal stem cells (MSCs) into germ cells. Because of immune-
modulating features, safety, and simple isolation, adipose tissue-derived MSCs (AT-MSCs) are good candidates for
such studies. However, low availability is the main limitation in using these cells. Different growth factors have been
investigated to overcome this issue. In the present study, we aimed to comparatively assess the performance of
AT-MSCs cultured under the presence or absence of three different growth factors, epidermal growth factor (EGF),
leukemia inhibitory factor (LIF) and glial cell line-derived neurotrophic factor (GDNF), following transplantation in
testicular torsion-detorsion mice
Materials and Methods This was an experimental study in which AT-MSCs were first isolated from male Naval
Medical Research Institute (NMRI) mice. Then, the mice underwent testicular torsion-detorsion surgery and received
bromodeoxyuridine (BrdU)-labeled AT-MSCs into the lumen of seminiferous tubules. The transplanted cells had been
cultured in different conditioned media, containing the three growth factors and without them. The expression of germ
cell-specific markers was evaluated with real-time polymerase chain reaction (PCR) and western-blot. Moreover,
immunohistochemical staining was used to trace the labeled cells.
Results The number of transplanted AT-MSCs resided in the basement membrane of seminiferous tubules significantly
increased after 8 weeks. The expression levels of Gcnf and Mvh genes in the transplanted testicles by AT-MSCs
cultured in the growth factors-supplemented medium was greater than those in the control group (P<0.001 and P<0.05,
respectively). The expression levels of the c-Kit and Scp3 genes did not significantly differ from the control group.
Conclusion Our findings showed that the use of EGF, LIF and GDNF to culture AT-MSCs can be very helpful in terms of
MSC survival and localization.
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Affiliation(s)
- Masoumeh Eliyasi Dashtaki
- Cellular and Molecular Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masoud Hemadi
- Cellular and Molecular Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ghasem Saki
- Physiology Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Electronic Address:
| | - Javad Mohammadiasl
- Department of Medical Genetics, School of Medicine, Ahvaz University of Medical Sciences, Ahvaz, Iran
| | - Ali Khodadadi
- Cancer, Environmental and Petroleum Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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21
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Rahmani F, Movahedin M, Mazaheri Z, Soleimani M. Transplantation of mouse iPSCs into testis of azoospermic mouse model: in vivo and in vitro study. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:1585-1594. [PMID: 31007064 DOI: 10.1080/21691401.2019.1594854] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
This study aimed to induce spermatogenesis in azoospermic testis through induced pluripotent stem cells (iPSCs) derived spermatogonial stem cell-like cells (SSCLCs) after iPSCs in vivo and in vitro transplantation and three-dimensional organ culture. DiI-labelled mouse iPSCs were transplanted to azoospermic testis mouse model (pretreated by busulfan 40 mg/kg). This study was designed based on two experimental groups. In experimental group 1(in vivo) labelled iPSCs were transplanted to azoospermic host testis. In experimental group 2 (in vitro) after cell transplantation, fragments of host testes were set as 3D organ culture and testis without cells transplantation served as the control group by the same method. The samples were evaluated by tracing DiI, cell homing, immunohistochemistry, and quantitative RT PCR assays. 2 weeks after iPSCs transplantation, the molecular assessment showed that Plzf, Thy1, Vasa and Gfra1 expression were increased significantly (p ≤ .05) in host testis and labelled iPSCs co-localized by the Plzf and Thy1 markers expression in the base of seminiferous tubules. These findings suggest the ability of iPSCs to achieve homing in the testis niche and indicate the critical inductive role of microenvironment signals in the differentiation of iPSCs to spermatogonial stem cell-like cells.
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Affiliation(s)
- Forouzan Rahmani
- a Department of Anatomical Sciences, Faculty of Medical Science , Tarbiat Modares University , Tehran , Iran
| | - Mansoureh Movahedin
- a Department of Anatomical Sciences, Faculty of Medical Science , Tarbiat Modares University , Tehran , Iran
| | - Zohreh Mazaheri
- b Department of Anatomical Sciences, Basic Medical Research Center , Histogenotech Company , Tehran , Iran
| | - Masoud Soleimani
- c Department of Hematology and Stem Cell Therapy, Faculty of Medical Science , Tarbiat Modares University , Tehran , Iran
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22
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Azizi H, Ghasemi Hamidabadi H, Skutella T. Differential Proliferation Effects after Short-Term Cultivation of Mouse Spermatogonial Stem Cells on Different Feeder Layers. CELL JOURNAL 2019; 21:186-193. [PMID: 30825292 PMCID: PMC6397599 DOI: 10.22074/cellj.2019.5802] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 08/21/2018] [Indexed: 01/10/2023]
Abstract
Objective Spermatogonial stem cells (SSCs) provide the cellular basis for sperm production transforming the male’s genetic
information to the next generation. We aimed to examine the effect of different feeder layer on proliferation of SSCs.
Materials and Methods In this experimental study, we compared the in vitro effects of the co-culture of mouse
SSCs with mouse embryonic fibroblasts (MEFs), sandos inbred mice (SIM) embryo-derived thioguanine- and ouabain-
resistant (STO) feeders, and neonate and adult testicular stroma cell (TSC) feeders on the efficiency of mouse SSC
proliferation and colony formation. Cells were cultivated on top of MEFs, STO, and neonate and adult TSCs feeder
layers for 30 days. The number and diameter of colonies and also the number of cells were evaluated during day 7, 15,
25, and 30 of culture. The mRNA expression of germ cells and somatic cells were analyzed.
Results In our study, we observed a significant difference in the proliferation rates and colony size of SSCs among
the groups, especially for MEFs (P<0.05). SSCs can proliferate on MEFS, but not on STO, neonate or adult TSCs.
Using immunocytochemistry by KI67 the proliferative activities of SSC colonies on MEFs were confirmed. The results
of Fluidigm real-time polymerase chain reaction (RT-PCR) showed a high expression of the germ cell genes the
promyelocytic leukemia zinc finger protein (PLZF), deleted in azoospermia-like (DAZL), octamer-binding transcription
factor 4 (OCT4), and DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 (DDX4 or VASA) in SSCs, and a low expression of
these genes in the feeder layers. Furthermore, we observed a higher expression of vimentin and integrin-B1 in feeder
layers than in SSCs (P<0.05).
Conclusion Based on the optimal effect of MEFs for better colonization of SSCs, these feeder cells seem to be
appropriate candidates for SSC cultures prior to transplantation. Therefore, it is suggested using these feeder cells for
SSC cultivation.
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Affiliation(s)
- Hossein Azizi
- Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran. Electronic Address:
| | - Hatef Ghasemi Hamidabadi
- Department of Anatomy and Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetic Research Center, Department of Anatomy and Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Thomas Skutella
- Institute for Anatomy and Cell Biology III, Medical Faculty, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany
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23
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Meligy FY, Abo Elgheed AT, Alghareeb SM. Therapeutic effect of adipose-derived mesenchymal stem cells on Cisplatin induced testicular damage in adult male albino rat. Ultrastruct Pathol 2019; 43:28-55. [DOI: 10.1080/01913123.2019.1572256] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Fatma Y. Meligy
- Histology and Cell Biology Department, Assiut University, Assiut, Egypt
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Gauthier-Fisher A, Szaraz P, Librach CL. Pericytes in the Umbilical Cord. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1122:211-233. [DOI: 10.1007/978-3-030-11093-2_12] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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25
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Fazeli Z, Abedindo A, Omrani MD, Ghaderian SMH. Mesenchymal Stem Cells (MSCs) Therapy for Recovery of Fertility: a Systematic Review. Stem Cell Rev Rep 2018; 14:1-12. [PMID: 28884412 DOI: 10.1007/s12015-017-9765-x] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In recent years, the mesenchymal stem cells (MSCs) have provided the new opportunities to treat different disorders including infertility. Different studies have suggested that the MSCs have ability to differentiate into germ-like cells under specific induction conditions as well as transplantation to gonadal tissues. The aim of this systematic review was to evaluate the results obtained from different studies on MSCs therapy for promoting fertility. This search was done in PubMed and Science Direct databases using key words MSCs, infertility, therapy, germ cell, azoospermia, ovarian failure and mesenchymal stem cell. Among the more than 11,400 papers, 53 studies were considered eligible for more evaluations. The obtained results indicated that the most studies were performed on MSCs derived from bone marrow and umbilical cord as compared with the other types of MSCs. Different evaluations on animal models as well as in vitro studies supported from their role in the recovery of spermatogenesis and folliculogenesis. Although the data obtained from this systematic review are promising, but the further studies need to assess the efficiency and safety of transplantation of these cells in fertility recovery.
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Affiliation(s)
- Zahra Fazeli
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Atieh Abedindo
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mir Davood Omrani
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, No 23, Shahid Labbafi Nejad Educational Hospital, Amir Ebrahimi St, Pasdaran Ave, Tehran, Iran
| | - Sayyed Mohammad Hossein Ghaderian
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, No 23, Shahid Labbafi Nejad Educational Hospital, Amir Ebrahimi St, Pasdaran Ave, Tehran, Iran
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Spermatogonial stem cell transplantation and male infertility: Current status and future directions. Arab J Urol 2017; 16:171-180. [PMID: 29713548 PMCID: PMC5922182 DOI: 10.1016/j.aju.2017.11.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 11/25/2017] [Accepted: 11/26/2017] [Indexed: 01/07/2023] Open
Abstract
Objective To summarise the current state of research into spermatogonial stem cell (SSC) therapies with a focus on future directions, as SSCs show promise as a source for preserving or initiating fertility in otherwise infertile men. Materials and methods We performed a search for publications addressing spermatogonial stem cell transplantation in the treatment of male infertility. The search engines PubMed and Google Scholar were used from 1990 to 2017. Search terms were relevant for spermatogonial stem cell therapies. Titles of publications were screened for relevance; abstracts were read, if related and full papers were reviewed for directly pertinent original research. Results In all, 58 papers were found to be relevant to this review, and were included in appropriate subheadings. This review discusses the various techniques that SSCs are being investigated to treat forms of male infertility. Conclusions Evidence does not yet support clinical application of SSCs in humans. However, significant progress in the in vitro and in vivo development of SSCs, including differentiation into functional germ cells, gives reason for cautious optimism for future research.
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Key Words
- ART, assisted reproductive technologies
- Allograft
- BMP4, bone morphogenetic protein 4
- Bcl6b, B-Cell CLL/Lymphoma 6B
- CD(24)(34), cluster of differentiation (24)(34)
- FGF2, Fibroblast growth factor 2
- FISH, fluorescence in situ hybridisation
- Fertility preservation
- GDNF, glial cell line-derived neurotrophic factor
- ICSI, intracytoplasmic sperm injection
- ID4, inhibitor of differentiation 4
- KS, Klinefelter syndrome
- Male infertility
- Non-obstructive azoospermia
- Onco-fertility
- PGC, primordial germ cells
- PLZF, promyelocytic leukaemia zinc finger
- PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses
- RA(R), retinoic acid (receptor)
- SPG, spermatogonia
- SSC, spermatogonial stem cell
- Stem cell therapy
- Stra8, stimulated by RA 8
- ZBTB, zinc finger and broad complex/Tramtrack/bric-a-brac
- c-Kit, KIT Proto-oncogene receptor tyrosine kinase
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Sharma S, Portela JMD, Langenstroth-Röwer D, Wistuba J, Neuhaus N, Schlatt S. Male germline stem cells in non-human primates. Primate Biol 2017; 4:173-184. [PMID: 32110705 PMCID: PMC7041516 DOI: 10.5194/pb-4-173-2017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 07/17/2017] [Indexed: 12/22/2022] Open
Abstract
Over the past few decades, several studies have attempted to decipher the
biology of mammalian germline stem cells (GSCs). These studies provide
evidence that regulatory mechanisms for germ cell specification and migration
are evolutionarily conserved across species. The characteristics and
functions of primate GSCs are highly distinct from rodent species; therefore
the findings from rodent models cannot be extrapolated to primates. Due to
limited availability of human embryonic and testicular samples for research
purposes, two non-human primate models (marmoset and macaque monkeys) are
extensively employed to understand human germline development and
differentiation. This review provides a broader introduction to the in vivo
and in vitro germline stem cell terminology from primordial to
differentiating germ cells. Primordial germ cells (PGCs) are the most
immature germ cells colonizing the gonad prior to sex differentiation into
testes or ovaries. PGC specification and migratory patterns among different
primate species are compared in the review. It also reports the distinctions
and similarities in expression patterns of pluripotency markers (OCT4A,
NANOG, SALL4 and LIN28) during embryonic developmental stages, among
marmosets, macaques and humans. This review presents a comparative summary
with immunohistochemical and molecular evidence of germ cell marker
expression patterns during postnatal developmental stages, among humans and
non-human primates. Furthermore, it reports findings from the recent
literature investigating the plasticity behavior of germ cells and stem cells
in other organs of humans and monkeys. The use of non-human primate models
would enable bridging the knowledge gap in primate GSC research and
understanding the mechanisms involved in germline development. Reported
similarities in regulatory mechanisms and germ cell expression profile in
primates demonstrate the preclinical significance of monkey models for
development of human fertility preservation strategies.
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Affiliation(s)
- Swati Sharma
- Center of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Medicine, Albert Schweitzer Campus 1, Building D11, Münster, Germany.,These authors contributed equally to this work
| | - Joana M D Portela
- Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.,These authors contributed equally to this work
| | - Daniel Langenstroth-Röwer
- Center of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Medicine, Albert Schweitzer Campus 1, Building D11, Münster, Germany
| | - Joachim Wistuba
- Center of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Medicine, Albert Schweitzer Campus 1, Building D11, Münster, Germany
| | - Nina Neuhaus
- Center of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Medicine, Albert Schweitzer Campus 1, Building D11, Münster, Germany
| | - Stefan Schlatt
- Center of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Medicine, Albert Schweitzer Campus 1, Building D11, Münster, Germany
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