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1
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Cheng H, Shang D, Zhou R. Germline stem cells in human. Signal Transduct Target Ther 2022; 7:345. [PMID: 36184610 PMCID: PMC9527259 DOI: 10.1038/s41392-022-01197-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/06/2022] [Accepted: 09/14/2022] [Indexed: 12/02/2022] Open
Abstract
The germline cells are essential for the propagation of human beings, thus essential for the survival of mankind. The germline stem cells, as a unique cell type, generate various states of germ stem cells and then differentiate into specialized cells, spermatozoa and ova, for producing offspring, while self-renew to generate more stem cells. Abnormal development of germline stem cells often causes severe diseases in humans, including infertility and cancer. Primordial germ cells (PGCs) first emerge during early embryonic development, migrate into the gentile ridge, and then join in the formation of gonads. In males, they differentiate into spermatogonial stem cells, which give rise to spermatozoa via meiosis from the onset of puberty, while in females, the female germline stem cells (FGSCs) retain stemness in the ovary and initiate meiosis to generate oocytes. Primordial germ cell-like cells (PGCLCs) can be induced in vitro from embryonic stem cells or induced pluripotent stem cells. In this review, we focus on current advances in these embryonic and adult germline stem cells, and the induced PGCLCs in humans, provide an overview of molecular mechanisms underlying the development and differentiation of the germline stem cells and outline their physiological functions, pathological implications, and clinical applications.
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Affiliation(s)
- Hanhua Cheng
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, 430072, Wuhan, China.
| | - Dantong Shang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, 430072, Wuhan, China
| | - Rongjia Zhou
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Renmin Hospital of Wuhan University, Wuhan University, 430072, Wuhan, China.
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2
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Lawlor M, Zigo M, Kerns K, Cho IK, Easley IV CA, Sutovsky P. Spermatozoan Metabolism as a Non-Traditional Model for the Study of Huntington’s Disease. Int J Mol Sci 2022; 23:ijms23137163. [PMID: 35806166 PMCID: PMC9266437 DOI: 10.3390/ijms23137163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
Huntington’s Disease (HD) is a fatal autosomal dominant neurodegenerative disease manifested through motor dysfunction and cognitive deficits. Decreased fertility is also observed in HD animal models and HD male patients, due to altered spermatogenesis and sperm function, thus resulting in reduced fertilization potential. Although some pharmaceuticals are currently utilized to mitigate HD symptoms, an effective treatment that remedies the pathogenesis of the disease is yet to be approved by the FDA. Identification of genes and relevant diagnostic biomarkers and therapeutic target pathways including glycolysis and mitochondrial complex-I-dependent respiration may be advantageous for early diagnosis, management, and treatment of the disease. This review addresses the HD pathway in neuronal and sperm metabolism, including relevant gene and protein expression in both neurons and spermatozoa, indicated in the pathogenesis of HD. Furthermore, zinc-containing and zinc-interacting proteins regulate and/or are regulated by zinc ion homeostasis in both neurons and spermatozoa. Therefore, this review also aims to explore the comparative role of zinc in both neuronal and sperm function. Ongoing studies aim to characterize the products of genes implicated in HD pathogenesis that are expressed in both neurons and spermatozoa to facilitate studies of future treatment avenues in HD and HD-related male infertility. The emerging link between zinc homeostasis and the HD pathway could lead to new treatments and diagnostic methods linking genetic sperm defects with somatic comorbidities.
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Affiliation(s)
- Meghan Lawlor
- Division of Animal Science, University of Missouri, Columbia, MO 65211, USA; (M.L.); (M.Z.); (K.K.)
| | - Michal Zigo
- Division of Animal Science, University of Missouri, Columbia, MO 65211, USA; (M.L.); (M.Z.); (K.K.)
| | - Karl Kerns
- Division of Animal Science, University of Missouri, Columbia, MO 65211, USA; (M.L.); (M.Z.); (K.K.)
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - In Ki Cho
- Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, GA 30602, USA; (I.K.C.); (C.A.E.IV)
- Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA
| | - Charles A. Easley IV
- Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, GA 30602, USA; (I.K.C.); (C.A.E.IV)
- Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA
| | - Peter Sutovsky
- Division of Animal Science, University of Missouri, Columbia, MO 65211, USA; (M.L.); (M.Z.); (K.K.)
- Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, MO 65211, USA
- Correspondence: ; Tel.: +1-(573)-882-3329
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3
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Tran KTD, Valli-Pulaski H, Colvin A, Orwig KE. Male fertility preservation and restoration strategies for patients undergoing gonadotoxic therapies†. Biol Reprod 2022; 107:382-405. [PMID: 35403667 PMCID: PMC9382377 DOI: 10.1093/biolre/ioac072] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 11/22/2022] Open
Abstract
Medical treatments for cancers or other conditions can lead to permanent infertility. Infertility is an insidious disease that impacts not only the ability to have a biological child but also the emotional well-being of the infertile individuals, relationships, finances, and overall health. Therefore, all patients should be educated about the effects of their medical treatments on future fertility and about fertility preservation options. The standard fertility preservation option for adolescent and adult men is sperm cryopreservation. Sperms can be frozen and stored for a long period, thawed at a later date, and used to achieve pregnancy with existing assisted reproductive technologies. However, sperm cryopreservation is not applicable for prepubertal patients who do not yet produce sperm. The only fertility preservation option available to prepubertal boys is testicular tissue cryopreservation. Next-generation technologies are being developed to mature those testicular cells or tissues to produce fertilization-competent sperms. When sperm and testicular tissues are not available for fertility preservation, inducing pluripotent stem cells derived from somatic cells, such as blood or skin, may provide an alternative path to produce sperms through a process call in vitro gametogenesis. This review describes standard and experimental options to preserve male fertility as well as the experimental options to produce functional spermatids or sperms from immature cryopreserved testicular tissues or somatic cells.
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Affiliation(s)
- Kien T D Tran
- Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,Magee-Womens Research Institute, Pittsburgh, PA, USA
| | - Hanna Valli-Pulaski
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,Magee-Womens Research Institute, Pittsburgh, PA, USA
| | - Amanda Colvin
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,Magee-Womens Research Institute, Pittsburgh, PA, USA
| | - Kyle E Orwig
- Correspondence: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA 15213, USA. Tel: 412-641-2460; E-mail:
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4
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Kumar D, Talluri TR, Selokar NL, Hyder I, Kues WA. Perspectives of pluripotent stem cells in livestock. World J Stem Cells 2021; 13:1-29. [PMID: 33584977 PMCID: PMC7859985 DOI: 10.4252/wjsc.v13.i1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/28/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The recent progress in derivation of pluripotent stem cells (PSCs) from farm animals opens new approaches not only for reproduction, genetic engineering, treatment and conservation of these species, but also for screening novel drugs for their efficacy and toxicity, and modelling of human diseases. Initial attempts to derive PSCs from the inner cell mass of blastocyst stages in farm animals were largely unsuccessful as either the cells survived for only a few passages, or lost their cellular potency; indicating that the protocols which allowed the derivation of murine or human embryonic stem (ES) cells were not sufficient to support the maintenance of ES cells from farm animals. This scenario changed by the innovation of induced pluripotency and by the development of the 3 inhibitor culture conditions to support naïve pluripotency in ES cells from livestock species. However, the long-term culture of livestock PSCs while maintaining the full pluripotency is still challenging, and requires further refinements. Here, we review the current achievements in the derivation of PSCs from farm animals, and discuss the potential application areas.
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Affiliation(s)
- Dharmendra Kumar
- Animal Physiology and Reproduction Division, ICAR-Central Institute for Research on Buffaloes, Hisar 125001, India.
| | - Thirumala R Talluri
- Equine Production Campus, ICAR-National Research Centre on Equines, Bikaner 334001, India
| | - Naresh L Selokar
- Animal Physiology and Reproduction Division, ICAR-Central Institute for Research on Buffaloes, Hisar 125001, India
| | - Iqbal Hyder
- Department of Physiology, NTR College of Veterinary Science, Gannavaram 521102, India
| | - Wilfried A Kues
- Department of Biotechnology, Friedrich-Loeffler-Institute, Federal Institute of Animal Health, Neustadt 31535, Germany
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5
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Approaches and Technologies in Male Fertility Preservation. Int J Mol Sci 2020; 21:ijms21155471. [PMID: 32751826 PMCID: PMC7432867 DOI: 10.3390/ijms21155471] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/21/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
Male fertility preservation is required when treatment with an aggressive chemo-/-radiotherapy, which may lead to irreversible sterility. Due to new and efficient protocols of cancer treatments, surviving rates are more than 80%. Thus, these patients are looking forward to family life and fathering their own biological children after treatments. Whereas adult men can cryopreserve their sperm for future use in assistance reproductive technologies (ART), this is not an option in prepubertal boys who cannot produce sperm at this age. In this review, we summarize the different technologies for male fertility preservation with emphasize on prepubertal, which have already been examined and/or demonstrated in vivo and/or in vitro using animal models and, in some cases, using human tissues. We discuss the limitation of these technologies for use in human fertility preservation. This update review can assist physicians and patients who are scheduled for aggressive chemo-/radiotherapy, specifically prepubertal males and their parents who need to know about the risks of the treatment on their future fertility and the possible present option of fertility preservation.
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Mahabadi JA, Sabzalipour H, Bafrani HH, Gheibi Hayat SM, Nikzad H. Application of induced pluripotent stem cell and embryonic stem cell technology to the study of male infertility. J Cell Physiol 2018; 233:8441-8449. [PMID: 29870061 DOI: 10.1002/jcp.26757] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 04/23/2018] [Indexed: 01/18/2023]
Abstract
Stem cells (SCs) are classes of undifferentiated biological cells existing only at the embryonic, fetal, and adult stages that can divide to produce specialized cell types during fetal development and remain in our bodies throughout life. The progression of regenerative and reproductive medicine owes the advancement of respective in vitro and in vivo biological science on the stem cell nature under appropriate conditions. The SCs are promising therapeutic tools to treat currently of infertility because of wide sources and high potency to differentiate. Nevertheless, no effective remedies are available to deal with severe infertility due to congenital or gonadotoxic stem cell deficiency in prepubertal childhood. Some recent solutions have been developed to address the severe fertility problems, including in vitro formation of germ cells from stem cells, induction of pluripotency from somatic cells, and production of patient-specific pluripotent stem cells. There is a possibility of fertility restoration using the in vitro formation of germ cells from somatic cells. Accordingly, the present review aimed at studying the literature published on the medical application of stem cells in reproductive concerns.
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Affiliation(s)
- Javad Amini Mahabadi
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Sabzalipour
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Seyed Mohammad Gheibi Hayat
- Student Research Committee, Department of Medical Biotechnology, Faculty Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Nikzad
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran
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7
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Amini Mahabadi J, Sabzalipoor H, Kehtari M, Enderami SE, Soleimani M, Nikzad H. Derivation of male germ cells from induced pluripotent stem cells by inducers: A review. Cytotherapy 2018; 20:279-290. [PMID: 29397308 DOI: 10.1016/j.jcyt.2018.01.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 11/15/2017] [Accepted: 01/01/2018] [Indexed: 12/29/2022]
Abstract
Induced pluripotent stem cells (iPSCs) refer to stem cells that are artificially produced using a new technology known as cellular reprogramming, which can use gene transduction in somatic cells. There are numerous potential applications for iPSCs in the field of stem cell biology becauase they are able to give rise to several different cell features of lineages such as three-germ layers. Primordial germ cells, generated via in vitro differentiation of iPSCs, have been demonstrated to produce functional gametes. Therefore, in this review we discussed past and recent advances in the in vitro differentiation of germ cells using pluripotent stem cells with an emphasis on iPSCs. Although this domain of research is still in its infancy, exploring development mechanisms of germ cells is promising, especially in humans, to promote future reproductive and developmental engineering technologies. While few studies have evaluated the ability and efficiency of iPSCs to differentiate toward male germ cells in vitro by different inducers, the given effect was investigated in this review.
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Affiliation(s)
- Javad Amini Mahabadi
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Sabzalipoor
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mousa Kehtari
- School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Seyed Ehsan Enderami
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Masoud Soleimani
- Hematology Department, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Nikzad
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran.
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8
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Fattahi A, Latifi Z, Ghasemnejad T, Nejabati HR, Nouri M. Insights into in vitro spermatogenesis in mammals: Past, present, future. Mol Reprod Dev 2017; 84:560-575. [DOI: 10.1002/mrd.22819] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Revised: 04/03/2017] [Accepted: 04/17/2017] [Indexed: 12/23/2022]
Affiliation(s)
- Amir Fattahi
- Institute for Stem Cell and Regenerative Medicine; Tabriz University of Medical Sciences; Tabriz Iran
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences; Tabriz University of Medical Sciences; Tabriz Iran
| | - Zeinab Latifi
- Department of Clinical Biochemistry, Faculty of Medicine; Tabriz University of Medical Sciences; Tabriz Iran
| | - Tohid Ghasemnejad
- Women's Reproductive Health Research Center; Tabriz University of Medical Sciences; Tabriz Iran
| | - Hamid Reza Nejabati
- Women's Reproductive Health Research Center; Tabriz University of Medical Sciences; Tabriz Iran
| | - Mohammad Nouri
- Department of Reproductive Biology, Faculty of Advanced Medical Sciences; Tabriz University of Medical Sciences; Tabriz Iran
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9
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Mouka A, Tachdjian G, Dupont J, Drévillon L, Tosca L. In Vitro Gamete Differentiation from Pluripotent Stem Cells as a Promising Therapy for Infertility. Stem Cells Dev 2016; 25:509-21. [PMID: 26873432 DOI: 10.1089/scd.2015.0230] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Generation of gametes derived in vitro from pluripotent stem cells holds promising prospects for future reproductive applications. Indeed, it provides information on molecular and cellular mechanisms underlying germ cell (GC) development and could offer a new potential treatment for infertility. Great progress has been made in derivation of gametes from embryonic stem cells, despite ethical issues. Induced pluripotent stem cells (iPSCs) technology allows the reprogramming of a differentiated somatic cell, possibly emanating from the patient, into a pluripotent state. With the emergence of iPSCs, several studies created primordial GC stage to mature gamete-like cells in vitro in mice and humans. Recent findings in GC derivation suggest that in mice, functional gametes can be generated in vitro. This strengthens the idea that it might be possible in the future to generate functional human sperm and oocytes from pluripotent stem cells in culture.
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Affiliation(s)
- Aurélie Mouka
- 1 AP-HP, Service d'Histologie, Embryologie et Cytogénétique, Hôpitaux Universitaires Paris-Sud , Clamart, France .,2 Université Paris-Sud , Le Kremlin-Bicêtre Cedex, France
| | - Gérard Tachdjian
- 1 AP-HP, Service d'Histologie, Embryologie et Cytogénétique, Hôpitaux Universitaires Paris-Sud , Clamart, France .,2 Université Paris-Sud , Le Kremlin-Bicêtre Cedex, France
| | - Joëlle Dupont
- 3 Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique , Nouzilly, France
| | - Loïc Drévillon
- 1 AP-HP, Service d'Histologie, Embryologie et Cytogénétique, Hôpitaux Universitaires Paris-Sud , Clamart, France
| | - Lucie Tosca
- 1 AP-HP, Service d'Histologie, Embryologie et Cytogénétique, Hôpitaux Universitaires Paris-Sud , Clamart, France .,2 Université Paris-Sud , Le Kremlin-Bicêtre Cedex, France
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10
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Gassei K, Orwig KE. Experimental methods to preserve male fertility and treat male factor infertility. Fertil Steril 2015; 105:256-66. [PMID: 26746133 DOI: 10.1016/j.fertnstert.2015.12.020] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 12/17/2015] [Accepted: 12/17/2015] [Indexed: 12/25/2022]
Abstract
Infertility is a prevalent condition that has insidious impacts on the infertile individuals, their families, and society, which extend far beyond the inability to have a biological child. Lifestyle changes, fertility treatments, and assisted reproductive technology (ART) are available to help many infertile couples achieve their reproductive goals. All of these technologies require that the infertile individual is able to produce at least a small number of functional gametes (eggs or sperm). It is not possible for a person who does not produce gametes to have a biological child. This review focuses on the infertile man and describes several stem cell-based methods and gene therapy approaches that are in the research pipeline and may lead to new fertility treatment options for men with azoospermia.
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Affiliation(s)
- Kathrin Gassei
- Department of Obstetrics, Gynecology and Reproductive Sciences and Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Kyle E Orwig
- Department of Obstetrics, Gynecology and Reproductive Sciences and Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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11
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Saito S, Lin YC, Murayama Y, Nakamura Y, Eckner R, Niemann H, Yokoyama KK. Retracted article: In vitro derivation of mammalian germ cells from stem cells and their potential therapeutic application. Cell Mol Life Sci 2015; 72:4545-60. [PMID: 26439925 PMCID: PMC4628088 DOI: 10.1007/s00018-015-2020-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Revised: 07/27/2015] [Accepted: 08/07/2015] [Indexed: 01/12/2023]
Abstract
Pluripotent stem cells (PSCs) are a unique type of cells because they
exhibit the characteristics of self-renewal and pluripotency. PSCs may be induced to
differentiate into any cell type, even male and female germ cells, suggesting their
potential as novel cell-based therapeutic treatment for infertility problems.
Spermatogenesis is an intricate biological process that starts from self-renewal of
spermatogonial stem cells (SSCs) and leads to differentiated haploid spermatozoa.
Errors at any stage in spermatogenesis may result in male infertility. During the
past decade, much progress has been made in the derivation of male germ cells from
various types of progenitor stem cells. Currently, there are two main approaches for
the derivation of functional germ cells from PSCs, either the induction of in vitro
differentiation to produce haploid cell products, or combination of in vitro
differentiation and in vivo transplantation. The production of mature and fertile
spermatozoa from stem cells might provide an unlimited source of autologous gametes
for treatment of male infertility. Here, we discuss the current state of the art
regarding the differentiation potential of SSCs, embryonic stem cells, and induced
pluripotent stem cells to produce functional male germ cells. We also discuss the
possible use of livestock-derived PSCs as a novel option for animal reproduction and
infertility treatment.
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Affiliation(s)
- Shigeo Saito
- Saito Laboratory of Cell Technology, Yaita, Tochigi, 329-1571, Japan. .,SPK Co., Ltd., Aizuwakamatsu, Fukushima, 965-0025, Japan. .,College of Engineering, Nihon University, Koriyama, Fukushima, 963-8642, Japan.
| | - Ying-Chu Lin
- School of Dentistry, College of Dental Medicine, Kaoshiung Medical University, 100 Shin-Chuan 1st Road, Kaohsiung, 807, Taiwan
| | - Yoshinobu Murayama
- College of Engineering, Nihon University, Koriyama, Fukushima, 963-8642, Japan
| | - Yukio Nakamura
- Cell Engineering Division, RIKEN BioResource Center, Tsukuba, 3050074, Japan
| | - Richard Eckner
- Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07101, USA
| | - Heiner Niemann
- Institute of Farm Animal Genetics, Friedrich-Löffler-Institut, Mariensee, 31535, Neustadt, Germany.
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine, Center of Stem Cell Research, Center of Environmental Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Rd, San Ming District, Kaohsiung, 807, Taiwan. .,Faculty of Science and Engineering, Tokushima Bunri University, Sanuki, 763-2193, Japan. .,Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
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12
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Zeng F, Huang F, Guo J, Hu X, Liu C, Wang H. Emerging methods to generate artificial germ cells from stem cells. Biol Reprod 2015; 92:89. [PMID: 25715792 DOI: 10.1095/biolreprod.114.124800] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Accepted: 02/16/2015] [Indexed: 12/29/2022] Open
Abstract
Germ cells are responsible for the transmission of genetic and epigenetic information across generations. At present, the number of infertile couples is increasing worldwide; these infertility problems can be traced to environmental pollutions, infectious diseases, cancer, psychological or work-related stress, and other factors, such as lifestyle and genetics. Notably, lack of germ cells and germ cell loss present real obstacles in infertility treatment. Recent research aimed at producing gametes through artificial germ cell generation from stem cells may offer great hope for affected couples to treat infertility in the future. Therefore, this rapidly emerging area of artificial germ cell generation from nongermline cells has gained considerable attention from basic and clinical research in the fields of stem cell biology, developmental biology, and reproductive biology. Here, we review the state of the art in artificial germ cell generation.
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Affiliation(s)
- Fanhui Zeng
- The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China
| | - Fajun Huang
- School of Medical Science, Hubei University for Nationalities, Enshi, China
| | - Jingjing Guo
- College of Life and Environmental Sciences, Shanghai Normal University, Shanghai, China
| | - Xingchang Hu
- College of Life and Environmental Sciences, Shanghai Normal University, Shanghai, China
| | - Changbai Liu
- The Institute of Molecular Biology, China Three Gorges University, Yichang, China
| | - Hu Wang
- Medical School, China Three Gorges University, Yichang, China
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13
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Easley CA, Bradner JM, Moser A, Rickman CA, McEachin ZT, Merritt MM, Hansen JM, Caudle WM. Assessing reproductive toxicity of two environmental toxicants with a novel in vitro human spermatogenic model. Stem Cell Res 2015; 14:347-55. [PMID: 25863443 DOI: 10.1016/j.scr.2015.03.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 03/16/2015] [Accepted: 03/17/2015] [Indexed: 11/26/2022] Open
Abstract
Environmental influences and insults by reproductive toxicant exposure can lead to impaired spermatogenesis or infertility. Understanding how toxicants disrupt spermatogenesis is critical for determining how environmental factors contribute to impaired fertility. While current animal models are available, understanding of the reproductive toxic effects on human fertility requires a more robust model system. We recently demonstrated that human pluripotent stem cells can differentiate into spermatogonial stem cells/spermatogonia, primary and secondary spermatocytes, and haploid spermatids; a model that mimics many aspects of human spermatogenesis. Here, using this model system, we examine the effects of 2-bromopropane (2-BP) and 1,2,dibromo-3-chloropropane (DBCP) on in vitro human spermatogenesis. 2-BP and DBCP are non-endocrine disrupting toxicants that are known to impact male fertility. We show that acute treatment with either 2-BP or DBCP induces a reduction in germ cell viability through apoptosis. 2-BP and DBCP affect viability of different cell populations as 2-BP primarily reduces spermatocyte viability, whereas DBCP exerts a much greater effect on spermatogonia. Acute treatment with 2-BP or DBCP also reduces the percentage of haploid spermatids. Both 2-BP and DBCP induce reactive oxygen species (ROS) formation leading to an oxidized cellular environment. Taken together, these results suggest that acute exposure with 2-BP or DBCP causes human germ cell death in vitro by inducing ROS formation. This system represents a unique platform for assessing human reproductive toxicity potential of various environmental toxicants in a rapid, efficient, and unbiased format.
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Affiliation(s)
- Charles A Easley
- Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
| | - Joshua M Bradner
- Department of Environmental Health, Rollins School of Public Heath, Emory University, Atlanta, GA 30322, USA; Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Amber Moser
- Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Chelsea A Rickman
- Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Zachary T McEachin
- Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering, Atlanta, GA 30332, USA
| | - Megan M Merritt
- Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jason M Hansen
- Division of Pulmonology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - W Michael Caudle
- Department of Environmental Health, Rollins School of Public Heath, Emory University, Atlanta, GA 30322, USA; Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA
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14
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Ishii T. Human iPS Cell-Derived Germ Cells: Current Status and Clinical Potential. J Clin Med 2014; 3:1064-83. [PMID: 26237592 PMCID: PMC4470171 DOI: 10.3390/jcm3041064] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 09/17/2014] [Accepted: 09/22/2014] [Indexed: 01/15/2023] Open
Abstract
Recently, fertile spermatozoa and oocytes were generated from mouse induced pluripotent (iPS) cells using a combined in vitro and in vivo induction system. With regard to germ cell induction from human iPS cells, progress has been made particularly in the male germline, demonstrating in vitro generation of haploid, round spermatids. Although iPS-derived germ cells are expected to be developed to yield a form of assisted reproductive technology (ART) that can address unmet reproductive needs, genetic and/or epigenetic instabilities abound in iPS cell generation and germ cell induction. In addition, there is still room to improve the induction protocol in the female germline. However, rapid advances in stem cell research are likely to make such obstacles surmountable, potentially translating induced germ cells into the clinical setting in the immediate future. This review examines the current status of the induction of germ cells from human iPS cells and discusses the clinical potential, as well as future directions.
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Affiliation(s)
- Tetsuya Ishii
- Office of Health and Safety, Hokkaido University, Sapporo 060-0808, Japan.
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15
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Irie N, Tang WWC, Azim Surani M. Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis. Reprod Med Biol 2014; 13:203-215. [PMID: 25298745 PMCID: PMC4182624 DOI: 10.1007/s12522-014-0184-2] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 05/19/2014] [Indexed: 12/01/2022] Open
Abstract
Germ cells are unique cell types that generate a totipotent zygote upon fertilization, giving rise to the next generation in mammals and many other multicellular organisms. How germ cells acquire this ability has been of considerable interest. In mammals, primordial germ cells (PGCs), the precursors of sperm and oocytes, are specified around the time of gastrulation. PGCs are induced by signals from the surrounding extra-embryonic tissues to the equipotent epiblast cells that give rise to all cell types. Currently, the mechanism of PGC specification in mammals is best understood from studies in mice. Following implantation, the epiblast cells develop as an egg cylinder while the extra-embryonic ectoderm cells which are the source of important signals for PGC specification are located over the egg cylinder. However, in most cases, including humans, the epiblast cells develop as a planar disc, which alters the organization and the source of the signaling for cell fates. This, in turn, might have an effect on the precise mechanism of PGC specification in vivo as well as in vitro using pluripotent embryonic stem cells. Here, we discuss how the key early embryonic differences between rodents and other mammals may affect the establishment of the pluripotency network in vivo and in vitro, and consequently the basis for PGC specification, particularly from pluripotent embryonic stem cells in vitro.
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Affiliation(s)
- Naoko Irie
- Wellcome Trust/Cancer Research UK, Gurdon InstituteUniversity of CambridgeTennis Court RoadCB2 1QNCambridgeUK
| | - Walfred W. C. Tang
- Wellcome Trust/Cancer Research UK, Gurdon InstituteUniversity of CambridgeTennis Court RoadCB2 1QNCambridgeUK
| | - M. Azim Surani
- Wellcome Trust/Cancer Research UK, Gurdon InstituteUniversity of CambridgeTennis Court RoadCB2 1QNCambridgeUK
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16
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Petkova R, Arabadjiev B, Chakarov S, Pankov R. Current state of the opportunities for derivation of germ-like cells from pluripotent stem cells: are you a man, or a mouse? BIOTECHNOL BIOTEC EQ 2014; 28:184-191. [PMID: 26019504 PMCID: PMC4434091 DOI: 10.1080/13102818.2014.907037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Accepted: 11/14/2013] [Indexed: 01/15/2023] Open
Abstract
The concept of pluripotency as a prerogative of cells of early mammal embryos and cultured embryonic stem cells (ESC) has been invalidated with the advent of induced pluripotent stem cells. Later, it became clear that the ability to generate all cell types of the adult organism is also a questionable aspect of pluripotency, as there are cell types, such as germ cells, which are difficult to produce from pluripotent stem cells. Recently it has been proposed that there are at least two different states of pluripotency; namely, the naïve, or ground state, and the primed state, which may differ radically in terms of timeline of existence, signalling mechanisms, cell properties, capacity for differentiation into different cell types, etc. Germ-like male and female rodent cells have been successfully produced in vitro from ESC and induced pluripotent stem cells. The attempts to derive primate primordial germ cells (PGC) and germ cells in vitro from pluripotent stem cells, however, still have a low success rate, especially with the female germline. The paper reviews the properties of rodent and primate ESC with regard to their capacity for differentiation in vitro to germ-like cells, outlining the possible caveats to derivation of PGC and germ cells from primate and human pluripotent cells.
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Affiliation(s)
- Rumena Petkova
- Scientific Technological Service (STS) Ltd., Sofia, Bulgaria
| | - Borislav Arabadjiev
- Scientific Technological Service (STS) Ltd., Sofia, Bulgaria
- Department of Cell Biology, Histology and Embryology, and Department of Biochemistry, Faculty of Biology, Sofia University ‘St. Kliment Ohridsky’, Sofia, Bulgaria
| | - Stoyan Chakarov
- Department of Cell Biology, Histology and Embryology, and Department of Biochemistry, Faculty of Biology, Sofia University ‘St. Kliment Ohridsky’, Sofia, Bulgaria
| | - Roumen Pankov
- Department of Cell Biology, Histology and Embryology, and Department of Biochemistry, Faculty of Biology, Sofia University ‘St. Kliment Ohridsky’, Sofia, Bulgaria
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17
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Easley CA, Latov DR, Simerly CR, Schatten G. Adult somatic cells to the rescue: nuclear reprogramming and the dispensability of gonadal germ cells. Fertil Steril 2014; 101:14-9. [PMID: 24382340 DOI: 10.1016/j.fertnstert.2013.11.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Revised: 11/13/2013] [Accepted: 11/18/2013] [Indexed: 01/04/2023]
Abstract
With advances in cancer therapies, survival rates in prepubescent patients have steadily increased. However, a number of these surviving patients have been rendered sterile owing to their rigorous oncologic treatment regimens. In addition to cancer treatments, men and women, who are genetically fertile, can become infertile owing to immune suppression treatments, exposure to environmental and industrial toxicants, and injury. Notwithstanding the great emotional burden from an inability to conceive a child with their partner, the financial burdens for testing and treatment are high, and successful treatment of these patients' sterility is rare. Recent advances in pluripotent stem cell differentiation and the generation of patient-specific, induced pluripotent stem cells indicate that stem cell replacement therapies or in vitro differentiation followed by IVF may be on the horizon. Here we discuss these recent advances, their relevance to treating male-factor and female-factor infertility, and what experimental procedures must be carried out in animal models before these exciting new treatments can be used in a clinical setting. The goal of this research is to generate functional gametes from no greater starting material than a mere skin biopsy.
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Affiliation(s)
- Charles A Easley
- Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia
| | - David R Latov
- Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia
| | - Calvin R Simerly
- Department of Obstetrics, Gynecology, & Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Magee Womens Research Institute, Pittsburgh Development Center, Pittsburgh, Pennsylvania
| | - Gerald Schatten
- Department of Obstetrics, Gynecology, & Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Magee Womens Research Institute, Pittsburgh Development Center, Pittsburgh, Pennsylvania.
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18
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Valli H, Phillips BT, Shetty G, Byrne JA, Clark AT, Meistrich ML, Orwig KE. Germline stem cells: toward the regeneration of spermatogenesis. Fertil Steril 2013; 101:3-13. [PMID: 24314923 DOI: 10.1016/j.fertnstert.2013.10.052] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 10/22/2013] [Accepted: 10/28/2013] [Indexed: 01/15/2023]
Abstract
Improved therapies for cancer and other conditions have resulted in a growing population of long-term survivors. Infertility is an unfortunate side effect of some cancer therapies that impacts the quality of life of survivors who are in their reproductive or prereproductive years. Some of these patients have the opportunity to preserve their fertility using standard technologies that include sperm, egg, or embryo banking, followed by IVF and/or ET. However, these options are not available to all patients, especially the prepubertal patients who are not yet producing mature gametes. For these patients, there are several stem cell technologies in the research pipeline that may give rise to new fertility options and allow infertile patients to have their own biological children. We will review the role of stem cells in normal spermatogenesis as well as experimental stem cell-based techniques that may have potential to generate or regenerate spermatogenesis and sperm. We will present these technologies in the context of the fertility preservation paradigm, but we anticipate that they will have broad implications for the assisted reproduction field.
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Affiliation(s)
- Hanna Valli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Magee-Womens Research Institute, Pittsburgh, Pennsylvania
| | - Bart T Phillips
- Department of Obstetrics, Gynecology and Reproductive Sciences, Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Magee-Womens Research Institute, Pittsburgh, Pennsylvania
| | - Gunapala Shetty
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - James A Byrne
- Department of Molecular and Medical Pharmacology, Center for Health Sciences, Los Angeles, California; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California
| | - Amander T Clark
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California
| | - Marvin L Meistrich
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kyle E Orwig
- Department of Obstetrics, Gynecology and Reproductive Sciences, Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
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19
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Imamura M, Hikabe O, Lin ZYC, Okano H. Generation of germ cells in vitro in the era of induced pluripotent stem cells. Mol Reprod Dev 2013; 81:2-19. [PMID: 23996404 DOI: 10.1002/mrd.22259] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 08/21/2013] [Indexed: 01/15/2023]
Abstract
Induced pluripotent stem cells (iPSCs) are stem cells that can be artificially generated via "cellular reprogramming" using gene transduction in somatic cells. iPSCs have enormous potential in stem-cell biology as they can give rise to numerous cell lineages, including the three germ layers. An evaluation of germ-line competency by blastocyst injection or tetraploid complementation, however, is critical for determining the developmental potential of mouse iPSCs towards germ cells. Recent studies have demonstrated that primordial germ cells obtained by the in vitro differentiation of iPSCs produce functional gametes as well as healthy offspring. These findings illustrate not only that iPSCs are developmentally similar to embryonic stem cells (ESCs), but also that somatic cells from adult tissues can produce gametes in vitro, that is, if they are reprogrammed into iPSCs. In this review, we discuss past and recent advances in the in vitro differentiation of germ cells using pluripotent stem cells, with an emphasis on ESCs and iPSCs. While this field of research is still at a stage of infancy, it holds great promises for investigating the mechanisms of germ-cell development, especially in humans, and for advancing reproductive and developmental engineering technologies in the future.
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Affiliation(s)
- Masanori Imamura
- Department of Physiology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan
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20
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Pera RAR. Status of human germ cell differentiation from pluripotent stem cells. Reprod Fertil Dev 2013; 25:396-404. [PMID: 23445816 DOI: 10.1071/rd12047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2012] [Accepted: 03/31/2012] [Indexed: 11/23/2022] Open
Abstract
Historically, the quality of life of infertile couples has been greatly diminished by the loss of opportunity to conceive. However, beginning with the advent of IVF in the late 1970s, novel clinical interventions have greatly changed the outlook for those with severe forms of infertility. Yet, in cases in which the quality and quantity of germ cells are most compromised, there are few options. In the present paper, the current status of germ cell development from stem cells is reviewed in light of potential utility for basic science and clinical applications.
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Affiliation(s)
- Renee A Reijo Pera
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University, Stanford, CA 94305-5463, USA.
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21
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Easley CA, Simerly CR, Schatten G. Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility? Reprod Biomed Online 2013; 27:75-80. [PMID: 23664220 DOI: 10.1016/j.rbmo.2013.03.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Revised: 03/11/2013] [Accepted: 03/14/2013] [Indexed: 01/15/2023]
Abstract
Recent advances in assisted reproduction treatment have enabled some couples with severe infertility issues to conceive, but the methods are not successful in all cases. Notwithstanding the significant financial burden of assisted reproduction treatment, the emotional scars from an inability to conceive a child enacts a greater toll on affected couples. While methods have circumvented some root causes for male and female infertility, often the underlying causes cannot be treated, thus true cures for restoring a patient's fertility are limited. Furthermore, the procedures are only available if the affected patients are able to produce gametes. Patients rendered sterile by medical interventions, exposure to toxicants or genetic causes are unable to utilize assisted reproduction to conceive a child - and often resort to donors, where permitted. Stem cells represent a future potential avenue for allowing these sterile patients to produce offspring. Advances in stem cell biology indicate that stem cell replacement therapies or in-vitro differentiation may be on the horizon to treat and could cure male and female infertility, although significant challenges need to be met before this technology can reach clinical practice. This article discusses these advances and describes the impact that these advances may have on treating infertility.
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Affiliation(s)
- Charles A Easley
- Laboratory of Translational Cell Biology, Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
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22
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Teramura T, Sugimoto H, Frampton J, Kida Y, Nakano M, Kawakami M, Izumi H, Fukunaga N, Onodera Y, Takehara T, Fukuda K, Hosoi Y. Generation of embryonic stem cell lines from immature rabbit ovarian follicles. Stem Cells Dev 2013; 22:928-38. [PMID: 23072728 DOI: 10.1089/scd.2012.0300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
In mammalian ovaries, many immature follicles remain after the dominant follicles undergo ovulation. Here we report the successful production of rabbit embryonic stem cells (ESCs) from oocytes produced by in vitro culture of immature follicles and subsequent in vitro maturation treatment. In total, we obtained 53 blastocysts from oocytes that received intracytoplasmic sperm injection followed by in vitro culture. Although only weak expression of POU5f1 was observed in the inner cell masses of in-vitro-cultured follicle-derived embryos, repeated careful cloning enabled establishment of 3 stable ESC lines. These ESC lines displayed the morphological characteristics of primed pluripotent stem cells. The ESC lines also expressed the pluripotent markers Nanog, POU5f1, and Sox2. Further, these ESCs could be differentiated into each of the 3 different germ layers both in vitro and in vivo. These results demonstrate that immature follicles from rabbits can be used to generate ESCs. Moreover, the use of rabbit oocytes as a cell source provides an experimental system that closely matches human reproductive and stem cell physiology.
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Affiliation(s)
- Takeshi Teramura
- Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kinki University Faculty of Medicine, Osaka, Japan.
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23
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Teramura T, Frampton J. Induced pluripotent stem cells in reproductive medicine. Reprod Med Biol 2012; 12:39-46. [PMID: 29699129 DOI: 10.1007/s12522-012-0141-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 11/29/2012] [Indexed: 01/25/2023] Open
Abstract
Despite recent advances in reproductive medicine, there are still no effective treatments for severe infertility caused by congenital absence of germ cells or gonadotoxic treatments during prepubertal childhood. However, the development of technologies for germ cell formation from stem cells in vitro, induction of pluripotency from somatic cells, and production of patient-specific pluripotent stem cells may provide new solutions for treating these severe fertility problems. It may be possible to produce germ cells in vitro from our own somatic cells that can be used to restore fertility. In addition, these technologies may also bring about novel therapies by helping to elucidate the mechanisms of human germ cell development. In this review, we describe the current approaches for obtaining germ cells from pluripotent stem cells, and provide basic information about induction of pluripotency and germ cell development.
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Affiliation(s)
- Takeshi Teramura
- Institute of Advanced Clinical Medicine Kinki University Faculty of Medicine 377-2 Osaka-sayama Osaka Japan.,Department of Obstetrics and Gynecology Mie University Faculty of Medicine Tsu Mie Japan
| | - John Frampton
- Department of Biomedical Engineering University of Michigan Ann Arbor MI USA
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24
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Easley CA, Phillips BT, McGuire MM, Barringer JM, Valli H, Hermann BP, Simerly CR, Rajkovic A, Miki T, Orwig KE, Schatten GP. Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Rep 2012; 2:440-6. [PMID: 22921399 DOI: 10.1016/j.celrep.2012.07.015] [Citation(s) in RCA: 174] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 06/12/2012] [Accepted: 07/31/2012] [Indexed: 12/25/2022] Open
Abstract
Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been shown to differentiate into primordial germ cells (PGCs) but not into spermatogonia, haploid spermatocytes, or spermatids. Here, we show that hESCs and hiPSCs differentiate directly into advanced male germ cell lineages, including postmeiotic, spermatid-like cells, in vitro without genetic manipulation. Furthermore, our procedure mirrors spermatogenesis in vivo by differentiating PSCs into UTF1-, PLZF-, and CDH1-positive spermatogonia-like cells; HIWI- and HILI-positive spermatocyte-like cells; and haploid cells expressing acrosin, transition protein 1, and protamine 1 (proteins that are uniquely found in spermatids and/or sperm). These spermatids show uniparental genomic imprints similar to those of human sperm on two loci: H19 and IGF2. These results demonstrate that male PSCs have the ability to differentiate directly into advanced germ cell lineages and may represent a novel strategy for studying spermatogenesis in vitro.
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Affiliation(s)
- Charles A Easley
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15108, USA
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25
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Germline development from human pluripotent stem cells toward disease modeling of infertility. Fertil Steril 2012; 97:1250-9. [DOI: 10.1016/j.fertnstert.2012.04.037] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 04/23/2012] [Accepted: 04/25/2012] [Indexed: 01/05/2023]
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26
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Characteristics of Novel Chicken Embryonic Stem Cells Established Using Chicken Leukemia Inhibitory Factor. J Poult Sci 2011. [DOI: 10.2141/jpsa.010102] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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27
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Fukunaga N, Teramura T, Onodera Y, Takehara T, Fukuda K, Hosoi Y. Leukemia inhibitory factor (LIF) enhances germ cell differentiation from primate embryonic stem cells. Cell Reprogram 2010; 12:369-76. [PMID: 20698776 DOI: 10.1089/cell.2009.0097] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Recently, several research groups have shown that germ cells can be produced in vitro from pluripotent embryonic stem cells (ESCs). In the mouse, live births of offspring using germ cells induced from ESCs in vitro have been reported. Furthermore, some efficient methods for inducing the useful number of germ cells from ESCs have also been developed. On the other hand, in primates, despite the appearances of germ cell-like cells including meiotic cells were observed by spontaneous differentiation or introducing transgenes, it has not been determined whether fully functional germ cells can be derived from ESCs. To elucidate the property for the germ cells induced from primate ESCs, specification of the promoting factors for the germ cell development and improving the efficiency of germ cell derivation are essential. Leukemia inhibitory factor (LIF) has been reported as one of the important factors for mouse primordial germ cell (PGC) survival in vitro. However, the effects of LIF on germ cell formation from pluripotent cells of primates have not been examined. The aim of this study is to determine whether LIF addition can improve in vitro germ cell production from cynomolgus monkey ESCs (cyESCs). After 8 days of differentiation, LIF added culture induced dome-shaped germ cell colonies as indicated by the intense expression of alkaline phosphatase activity (ALP). These cells also demonstrate high-level expression of the germ cell-marker VASA, OCT-4, and BLIMP-1, and show SSEA-1 expression that supports their early stage germ cell identity. Finally, we observed that adding LIF to differentiating cultures inhibited meiotic gene expressions and increased the percentage of ALP-positive cells, and demonstrate that the addition of LIF to differentiation media increases differentiation of early germ cells from the cyESCs.
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Affiliation(s)
- Naoto Fukunaga
- Department of Biology Oriented Science and Technology, Kinki University, Osaka, Japan
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28
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Systems biology discoveries using non-human primate pluripotent stem and germ cells: novel gene and genomic imprinting interactions as well as unique expression patterns. Stem Cell Res Ther 2010; 1:24. [PMID: 20699013 PMCID: PMC2941116 DOI: 10.1186/scrt24] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The study of pluripotent stem cells has generated much interest in both biology and medicine. Understanding the fundamentals of biological decisions, including what permits a cell to maintain pluripotency, that is, its ability to self-renew and thereby remain immortal, or to differentiate into multiple types of cells, is of profound importance. For clinical applications, pluripotent cells, including both embryonic stem cells and adult stem cells, have been proposed for cell replacement therapy for a number of human diseases and disorders, including Alzheimer's, Parkinson's, spinal cord injury and diabetes. One challenge in their usage for such therapies is understanding the mechanisms that allow the maintenance of pluripotency and controlling the specific differentiation into required functional target cells. Because of regulatory restrictions and biological feasibilities, there are many crucial investigations that are just impossible to perform using pluripotent stem cells (PSCs) from humans (for example, direct comparisons among panels of inbred embryonic stem cells from prime embryos obtained from pedigreed and fertile donors; genomic analysis of parent versus progeny PSCs and their identical differentiated tissues; intraspecific chimera analyses for pluripotency testing; and so on). However, PSCs from nonhuman primates are being investigated to bridge these knowledge gaps between discoveries in mice and vital information necessary for appropriate clinical evaluations. In this review, we consider the mRNAs and novel genes with unique expression and imprinting patterns that were discovered using systems biology approaches with primate pluripotent stem and germ cells.
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29
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Comparative evaluation of different in vitro systems that stimulate germ cell differentiation in human embryonic stem cells. Fertil Steril 2010; 93:986-94. [DOI: 10.1016/j.fertnstert.2008.10.030] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2008] [Revised: 10/14/2008] [Accepted: 10/17/2008] [Indexed: 01/15/2023]
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30
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Haston KM, Tung JY, Reijo Pera RA. Dazl functions in maintenance of pluripotency and genetic and epigenetic programs of differentiation in mouse primordial germ cells in vivo and in vitro. PLoS One 2009; 4:e5654. [PMID: 19468308 PMCID: PMC2681483 DOI: 10.1371/journal.pone.0005654] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2009] [Accepted: 04/27/2009] [Indexed: 11/19/2022] Open
Abstract
Background Mammalian germ cells progress through a unique developmental program that encompasses proliferation and migration of the nascent primordial germ cell (PGC) population, reprogramming of nuclear DNA to reset imprinted gene expression, and differentiation of mature gametes. Little is known of the genes that regulate quantitative and qualitative aspects of early mammalian germ cell development both in vivo, and during differentiation of germ cells from mouse embryonic stem cells (mESCs) in vitro. Methodology and Principal Findings We used a transgenic mouse system that enabled isolation of small numbers of Oct4ΔPE:GFP-positive germ cells in vivo, and following differentiation from mESCs in vitro, to uncover quantitate and qualitative phenotypes associated with the disruption of a single translational regulator, Dazl. We demonstrate that disruption of Dazl results in a post-migratory, pre-meiotic reduction in PGC number accompanied by aberrant expression of pluripotency genes and failure to erase and re-establish genomic imprints in isolated male and female PGCs, as well as subsequent defect in progression through meiosis. Moreover, the phenotypes observed in vivo were mirrored by those in vitro, with inability of isolated mutant PGCs to establish pluripotent EG (embryonic germ) cell lines and few residual Oct-4-expressing cells remaining after somatic differentiation of mESCs carrying a Dazl null mutation. Finally, we observed that even within undifferentiated mESCs, a nascent germ cell subpopulation exists that was effectively eliminated with ablation of Dazl. Conclusions and Significance This report establishes the translational regulator Dazl as a component of pluripotency, genetic, and epigenetic programs at multiple time points of germ cell development in vivo and in vitro, and validates use of the ESC system to model and explore germ cell biology.
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Affiliation(s)
- Kelly M. Haston
- Institute for Stem Cell Biology & Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Joyce Y. Tung
- Institute for Stem Cell Biology & Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Palo Alto, California, United States of America
| | - Renee A. Reijo Pera
- Institute for Stem Cell Biology & Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Palo Alto, California, United States of America
- * E-mail:
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Yamauchi K, Hasegawa K, Chuma S, Nakatsuji N, Suemori H. In vitro germ cell differentiation from cynomolgus monkey embryonic stem cells. PLoS One 2009; 4:e5338. [PMID: 19399191 PMCID: PMC2671468 DOI: 10.1371/journal.pone.0005338] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2008] [Accepted: 04/02/2009] [Indexed: 01/12/2023] Open
Abstract
Background Mouse embryonic stem (ES) cells can differentiate into female and male germ cells in vitro. Primate ES cells can also differentiate into immature germ cells in vitro. However, little is known about the differentiation markers and culture conditions for in vitro germ cell differentiation from ES cells in primates. Monkey ES cells are thus considered to be a useful model to study primate gametogenesis in vitro. Therefore, in order to obtain further information on germ cell differentiation from primate ES cells, this study examined the ability of cynomolgus monkey ES cells to differentiate into germ cells in vitro. Methods and Findings To explore the differentiation markers for detecting germ cells differentiated from ES cells, the expression of various germ cell marker genes was examined in tissues and ES cells of the cynomolgus monkey (Macaca fascicularis). VASA is a valuable gene for the detection of germ cells differentiated from ES cells. An increase of VASA expression was observed when differentiation was induced in ES cells via embryoid body (EB) formation. In addition, the expression of other germ cell markers, such as NANOS and PIWIL1 genes, was also up-regulated as the EB differentiation progressed. Immunocytochemistry identified the cells expressing stage-specific embryonic antigen (SSEA) 1, OCT-4, and VASA proteins in the EBs. These cells were detected in the peripheral region of the EBs as specific cell populations, such as SSEA1-positive, OCT-4-positive cells, OCT-4-positive, VASA-positive cells, and OCT-4-negative, VASA-positive cells. Thereafter, the effect of mouse gonadal cell-conditioned medium and growth factors on germ cell differentiation from monkey ES cells was examined, and this revealed that the addition of BMP4 to differentiating ES cells increased the expression of SCP1, a meiotic marker gene. Conclusion VASA is a valuable gene for the detection of germ cells differentiated from ES cells in monkeys, and the identification and characterization of germ cells derived from ES cells are possible by using reported germ cell markers in vivo, including SSEA1, OCT-4, and VASA, in vitro as well as in vivo. These findings are thus considered to help elucidate the germ cell developmental process in primates.
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Affiliation(s)
- Kaori Yamauchi
- Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
- Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Kouichi Hasegawa
- Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Shinichiro Chuma
- Department of Development and Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Norio Nakatsuji
- Department of Development and Differentiation, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
- Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Hirofumi Suemori
- Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
- * E-mail:
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Takehara T, Teramura T, Onodera Y, Kakegawa R, Fukunaga N, Takenoshita M, Sagawa N, Fukuda K, Hosoi Y. Rho-associated kinase inhibitor Y-27632 promotes survival of cynomolgus monkey embryonic stem cells. Mol Hum Reprod 2008; 14:627-34. [PMID: 18940855 PMCID: PMC2639404 DOI: 10.1093/molehr/gan061] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Non-human primates are suitable models for preclinical research aimed at cell-replacement therapies. Recently, it has been reported that Rho-associated kinase inhibitor Y-27632 markedly reduced dissociation-induced apoptosis of human embryonic stem (hES) cells, and is expected as a novel supplement for hES cell maintenance or differentiation inductions; however, the effects of the chemical are still to be determined in model animals. Here, we demonstrated the effect of Y-27632 on cynomolgus monkey ES (cyES) cells. Also, in cyES cells, Y-27632 treatment dramatically improved the efficiency of colony formation from single cells without affecting the pluripotent state and karyotype. Y-27632 supplementation was also effective for feeder-free culture and differentiation induction. Neural stem cells directly induced from cyES cells could give rise to neurons, astrocytes and dopamine producing cells. The present result not only suggests that the chemical was effective for improving the culture system of primate ES cells, but also the similarity between cyES and hES cells regarding the reactions to the chemical, which might be further evidence that cyES cells are superior models for hES cells.
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Affiliation(s)
- Toshiyuki Takehara
- Graduate School of Biology-Oriented Science and Technology, Kinki University, Nishimitani, Kinokawa, Wakayama 649-6493, Japan
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