Generic placeholder image

Current Stem Cell Research & Therapy


ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

General Review Article

Differentiation of Human Induced Pluripotent Stem Cells into Male Germ Cells

Author(s): Na Zhao, Min Sheng, Xia Wang, Yonghui Li* and Maryam Farzaneh*

Volume 16, Issue 5, 2021

Published on: 05 July, 2020

Page: [622 - 629] Pages: 8

DOI: 10.2174/1574888X15666200705214223

Price: $65


Infertility is defined as not being able to become pregnant or to conceive a child after one year or longer of regular unprotected intercourse. Male infertility refers to a male’s inability to cause pregnancy that can result from deficiencies in semen quality, sperm concentration, or abnormal sperm function. Till now, there are few effective methods for the treatment of a couple with male infertility. In the past few years, stem cell-based therapy as a promising strategy has emerged for the treatment of male infertility. Human Pluripotent Stem Cells (hPSCs) can self-renew and differentiate into any type of cell. Human Embryonic Stem Cells (hESCs) and induced Pluripotent Stem Cells (hiPSCs) are two pluripotent populations that can proliferate and give rise to ectodermal, mesodermal, endodermal, and germ cell lineages. Both undifferentiated hiPSCs and hESCs are powerful candidates for the treatment of male infertility. Generation of male germ cells from hPSCs can provide new mechanistic insights into the regulation of spermatogenesis and have a great opportunity for families with infertility. Therefore, a robust, reproducible, and low-cost culture method that supports hPSCs differentiation into male germ cells is necessary. However, very few studies have focused on the derivation of sperm-like cells from hiPSCs and the details of hPSCs differentiation into male germ cells have not been fully investigated. Therefore, in this review, we focus on the in vitro differentiation potential of hiPSCs into male germ cells.

Keywords: Human pluripotent stem cells, human embryonic stem cells, human induced pluripotent stem cells, male germ cells, differentiation, infertility.

Zegers-Hochschild F, Adamson GD, Dyer S, et al. The international glossary on infertility and fertility care, 2017. Hum Reprod 2017; 32(9): 1786-801.
[] [PMID: 29117321]
Vander Borght M, Wyns C. Fertility and infertility: Definition and epidemiology. Clin Biochem 2018; 62: 2-10.
[] [PMID: 29555319]
Shukla KK, Mahdi AA, Rajender S. Apoptosis, spermatogenesis and male infertility. Front Biosci (Elite Ed) 2012; 4: 746-54.
[] [PMID: 22201910]
Dohle GR, Smit M, Weber RF. Androgens and male fertility. World J Urol 2003; 21(5): 341-5.
[] [PMID: 14566423]
Anawalt BD, Page ST, Matsumoto AM. UpTodate Approach to the male with infertility Snyder PJ, Matsumoto AM, Eds Waltham, MA Available from:
Rumbold AR, Sevoyan A, Oswald TK, Fernandez RC, Davies MJ, Moore VM. Impact of male factor infertility on offspring health and development. Fertil Steril 2019; 111(6): 1047-53.
[] [PMID: 31155114]
Hussein MOM, Gadir MAGA, Hamad MNM, Alameen M. Occupation and male infertility among selected group of Sudanese patients with infertility disorders. Glob J Med Res 2018; 18(2E): 5-7.
Laan M. Systematic review of the monogenetic causes of male infertility: the first step towards diagnostic gene panels in the andrology clinic. Hum Reprod 2019 May 1; 34(5): 783-5.
Gonsalves J, Sun F, Schlegel PN, et al. Defective recombination in infertile men. Hum Mol Genet 2004; 13(22): 2875-83.
[] [PMID: 15385442]
Poongothai J, Gopenath TS, Manonayaki S. Genetics of human male infertility. Singapore Med J 2009; 50(4): 336-47.
[PMID: 19421675]
Marconi M, Weidner W. Site and risk factors of antisperm antibodies production in the male population. In: Krause WKH, Naz RK, Eds. Immune Infertility. Germany: Springer 2017; pp. 133-47.
Didwania A. Management of male infertility secondary to chemotherapeutic agents during childhood cancer treatment. In: Woodruff TK, Shah DK, Vitek WS, Eds. Textbook of oncofertility research and practice. Germany: Springer 2019; pp. 501-4.
Chakravarty B, Bhattacharya R, Chakraborty S, Bal R. Approach to Evaluation of Male Factor Infertility. In: Basu S, Mukherjee GG, Khastgir G, Eds. Practical Guide in Infertility. New Delhi, India: Jp Medical Pub 2018; pp. 1-9.
Choy JT, Eisenberg ML. Male infertility as a window to health. Fertil Steril 2018; 110(5): 810-4.
[] [PMID: 30316415]
Du Plessis SS, Cabler S, McAlister DA, Sabanegh E, Agarwal A. The effect of obesity on sperm disorders and male infertility. Nat Rev Urol 2010; 7(3): 153-61.
[] [PMID: 20157305]
Nagirnaja L, Aston KI, Conrad DF. Genetic intersection of male infertility and cancer. Fertil Steril 2018; 109(1): 20-6.
[] [PMID: 29307395]
Kumar N, Singh AK. Trends of male factor infertility, an important cause of infertility: A review of literature. J Hum Reprod Sci 2015; 8(4): 191-6.
[] [PMID: 26752853]
Barratt CLR, Björndahl L, De Jonge CJ, et al. The diagnosis of male infertility: An analysis of the evidence to support the development of global WHO guidance-challenges and future research opportunities. Hum Reprod Update 2017; 23(6): 660-80.
[] [PMID: 28981651]
Agarwal A, Majzoub A, Parekh N, Henkel R. A schematic overview of the current status of male infertility practice. World J Mens Health 2019; 38(3): 308-22.
[] [PMID: 31385475]
Ahmadi MH, Mirsalehian A, Sadighi GMA, Bahador A, Talebi M. Asymptomatic infection with Mycoplasma hominis negatively affects semen parameters and leads to male infertility as confirmed by improved semen parameters after antibiotic treatment. Urology 2017; 100: 97-102.
[] [PMID: 27871827]
Ahmadi MH, Mirsalehian A, Sadighi GMA, Bahador A, Afraz K. Association of asymptomatic Chlamydia trachomatis infection with male infertility and the effect of antibiotic therapy in improvement of semen quality in infected infertile men. Andrologia 2018; 50(4): e12944.
[] [PMID: 29292525]
Agarwal A, Rana M, Qiu E, AlBunni H, Bui AD, Henkel R. Role of oxidative stress, infection and inflammation in male infertility. Andrologia 2018; 50(11): e13126.
[] [PMID: 30569652]
Shah R. Surgical sperm retrieval: Techniques and their indications. Indian J Urol 2011; 27(1): 102-9.
Esteves SC, Varghese AC. Laboratory handling of epididymal and testicular spermatozoa: What can be done to improve sperm injections outcome. J Hum Reprod Sci 2012; 5(3): 233-43.
[] [PMID: 23533051]
Naser SSA, Alhabbash MI. Male infertility expert system diagnoses and treatment. Am J Innov Res Appl Sci 2016; 2(4): 181-92.
Luján S, Caroppo E, Niederberger C, et al. Sperm DNA methylation epimutation biomarkers for male infertility and fsh therapeutic responsiveness. Sci Rep 2019; 9(1): 16786.
[] [PMID: 31727924]
Laursen RJ, Elbaek HO, Povlsen BB, et al. Hormonal stimulation of spermatogenesis: A new way to treat the infertile male with non-obstructive azoospermia? Int Urol Nephrol 2019; 51(3): 453-6.
[] [PMID: 30756283]
Barbonetti A, Calogero AE, Balercia G, et al. The use of follicle stimulating hormone (FSH) for the treatment of the infertile man: Position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS). J Endocrinol Invest 2018; 41(9): 1107-22.
[] [PMID: 29392544]
Gregory A. Psychosexual therapy for male sexual dysfunction. In: Minhas S, John Mulhall, Eds. Male sexual dysfunction: a clinical guide. NJ, USA: Wiley 2017; pp. 133-42.
Schover LR. Sexual dysfunction. In: Bast RC, Jr, Croce CM, Hait WN, Eds. et al Holland‐Frei Cancer Medicine. NJ, USA: Wiley 2016; pp. 1-6.
Bao B, Shang J, Wang J, et al. Efficacy and safety of behavioral therapy for premature ejaculation: Protocol for a systematic review. Medicine 2019; 98(3): e14056.
[] [PMID: 30653115]
Ciocanel O, Power K, Eriksen A. Interventions to treat erectile dysfunction and premature ejaculation: An overview of systematic reviews. Sex Med 2019; 7(3): 251-69.
[] [PMID: 31300388]
Esteves SC, Roque M, Agarwal A. Outcome of assisted reproductive technology in men with treated and untreated varicocele: Systematic review and meta-analysis. Asian J Androl 2016; 18(2): 254-8.
[] [PMID: 26510504]
Nayan M, Punjani N, Grober E, Lo K, Jarvi K. The use of assisted reproductive technology before male factor infertility evaluation. Transl Androl Urol 2018; 7(4): 678-85.
[] [PMID: 30211059]
Volgsten H, Schmidt L, Skoog Svanberg A, Ekselius L, Sundström Poromaa I. Psychiatric disorders in women and men up to five years after undergoing assisted reproductive technology treatment-A prospective cohort study. Hum Fertil 2019; 22(4): 277-82.
[] [PMID: 29768933]
Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 2016; 79(3): 629-61.
[] [PMID: 26852623]
Nayernia K, Li M, Jaroszynski L, et al. Stem cell based therapeutical approach of male infertility by teratocarcinoma derived germ cells. Hum Mol Genet 2004; 13(14): 1451-60.
[] [PMID: 15163638]
Neuhaus N, Schlatt S. Stem cell-based options to preserve male fertility. Science 2019; 363(6433): 1283-4.
[] [PMID: 30898920]
Hendriks S, Dancet E, Vliegenthart R, Repping S. The acceptability of stem cell-based fertility treatments for different indications MHR: Basic science of reproductive medicine 2017; 23(12): 855-63.
Valli H, Gassei K, Orwig KE. Stem cell therapies for male infertility: Where are we now and where are we going? In: Carrell DT, Schlegel PN, Racowsky C, Gianaroli N, Eds. Biennial review of infertility. Switzerland: Springer 2015; pp. 17-39.
Dong L, Kristensen SG, Hildorf S, et al. Propagation of spermatogonial stem cell-like cells from infant boys. Front Physiol 2019; 10(1155): 1155.
[] [PMID: 31607938]
Yamada M, De Chiara L, Seandel M. Spermatogonial stem cells: Implications for genetic disorders and prevention. Stem Cells Dev 2016; 25(20): 1483-94.
[] [PMID: 27596369]
Murdock MH, David S, Swinehart IT, et al. Human testis extracellular matrix enhances human spermatogonial stem cell survival in vitro. Tissue Eng Part A 2019; 25(7-8): 663-76.
[] [PMID: 30311859]
Wang G, Farzaneh M. Mini review; differentiation of human pluripotent stem cells into oocytes. Curr Stem Cell Res Ther 2020; 15(4): 301-7.
[] [PMID: 31951188]
Zhu Z, Huangfu D. Human pluripotent stem cells: An emerging model in developmental biology. Development 2013; 140(4): 705-17.
[] [PMID: 23362344]
Biehl JK, Russell B. Introduction to stem cell therapy. J Cardiovasc Nurs 2009; 24(2): 98-103.
[] [PMID: 19242274]
Farzaneh M, Derakhshan Z, Hallajzadeh J, Sarani NH, Nejabatdoust A, Khoshnam SE. Suppression of TGF-β and ERK signaling pathways as a new strategy to provide rodent and non-rodent pluripotent stem cells. Curr Stem Cell Res Ther 2019; 14(6): 466-73.
[] [PMID: 30868962]
Kolagar TA, Farzaneh M, Nikkar N, Khoshnam SE, Khoshnam S. Human pluripotent stem cells in neurodegenerative diseases: Potentials, advances and limitations. Curr Stem Cell Res Ther 2020; 15(2): 102-10.
[] [PMID: 31441732]
An N, Yang J, Wang H, et al. Mechanism of mesenchymal stem cells in spinal cord injury repair through macrophage polarization. Cell & Bioscience 2021; 11: 1-14.
Alishahi M, Anbiyaiee A, Farzaneh M, Khoshnam SE. Human mesenchymal stem cells for spinal cord injury. Curr Stem Cell Res Ther 2020; 15(4): 340-8.
[] [PMID: 32178619]
Zhao Y, Liu H, Zhao C, Dang P, Li H, Farzaneh M. Paracrine interactions involved in human induced pluripotent stem cells differentiation into chondrocytes. Current stem cell research & therapy 2020; 15(3): 233-42.
[PMID: 31889496]
Farzaneh M, Anbiyaiee A, Khoshnam SE. Human pluripotent stem cells for spinal cord injury. Curr Stem Cell Res Ther 2020; 15(2): 135-43.
[] [PMID: 31656156]
Schwartz PH, Brick DJ, Nethercott HE, Stover AE. Traditional human embryonic stem cell culture. Methods Mol Biol 2011; 767: 107-23.
[] [PMID: 21822870]
Gavrilov S, Papaioannou VE, Landry DW. Alternative Sources of Human Embryonic Stem Cells. In: Atala A, Lanza R, Mikos T, Nerem R, Eds. Principles of Regenerative Medicine. Netherlands: Elsevier 2019; pp. 125-32.
Apáti Á, Varga N, Berecz T, Erdei Z, Homolya L, Sarkadi B. Application of human pluripotent stem cells and pluripotent stem cell-derived cellular models for assessing drug toxicity. Expert Opin Drug Metab Toxicol 2019; 15(1): 61-75.
[] [PMID: 30526128]
Plusa B, Hadjantonakis A-K. Embryonic stem cell identity grounded in the embryo. Nat Cell Biol 2014; 16(6): 502-4.
[] [PMID: 24875737]
Farzaneh M, Attari F, Khoshnam SE. Concise review: LIN28/let-7 signaling, a critical double-negative feedback loop during pluripotency, reprogramming, and tumorigenicity. Cell Reprogram 2017; 19(5): 289-93.
[] [PMID: 28846452]
Farzaneh M, Alishahi M, Derakhshan Z, Sarani NH, Attari F, Khoshnam SE. the expression and functional roles of miRNAs in embryonic and lineage-specific stem cells. Curr Stem Cell Res Ther 2019; 14(3): 278-89.
[] [PMID: 30674265]
Narsinh KH, Plews J, Wu JC. Comparison of human induced pluripotent and embryonic stem cells: Fraternal or identical twins? Mol Ther 2011; 19(4): 635-8.
[] [PMID: 21455209]
Chin MH, Mason MJ, Xie W, et al. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 2009; 5(1): 111-23.
[] [PMID: 19570518]
Karagiannis P. Clinical potential of induced pluripotent stem cells. In: Inoue H, Nakamura Y, Eds. Medical applications of iPS cells. Switzerland: Springer 2019; pp. 3-12.
Green RM. Ethical considerations. In: Atala A, Lanza R, Mikos T, Nerem R, Eds. Principles of Regenerative Medicine. Netherlands: Elsevier 2019; pp. 1331-43.
Watanabe N, Santostefano KE, Yachnis AT, Terada N. A pathologist's perspective on induced pluripotent stem cells. Lab Invest 2017; 97(10): 1126-32.
Doss MX, Sachinidis A. Current challenges of iPSC-based disease modeling and therapeutic implications. Cells 2019; 8(5): 403.
[] [PMID: 31052294]
Li P, Hu H, Yang S, et al. Differentiation of induced pluripotent stem cells into male germ cells in vitro through embryoid body formation and retinoic acid or testosterone induction. Biomed Res Int 2013; 2013: 608728.
Easley CA IV, Phillips BT, McGuire MM, et al. Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Rep 2012; 2(3): 440-6.
[] [PMID: 22921399]
Surani MA. Human germline: A new research frontier. Stem Cell Reports 2015; 4(6): 955-60.
[] [PMID: 26028529]
Sarkar S, Singh R. Primordial germ cells: Origin, migration and testicular development. In: Singh R, Ed. Molecular signaling in spermatogenesis and male infertility. Boca Raton: CRC Press 2019; pp. 1-9.
Fang F, Li Z, Zhao Q, Li H, Xiong C. Human induced pluripotent stem cells and male infertility: An overview of current progress and perspectives. Hum Reprod 2018; 33(2): 188-95.
[] [PMID: 29315416]
Patni P, Mohanty SK, Singh R. Embryonic development of the testis. In: Singh K, Singh K, Eds. Male infertility: understanding, causes and treatment. Germany: Springer 2017; pp. 13-24.
Petersen PM, Seierøe K, Pakkenberg B. The total number of Leydig and Sertoli cells in the testes of men across various age groups-A stereological study. J Anat 2015; 226(2): 175-9.
[] [PMID: 25545958]
Mäkelä J-A, Koskenniemi JJ, Virtanen HE, Toppari J. Testis development. Endocr Rev 2019; 40(4): 857-905.
[] [PMID: 30590466]
Griswold MD. Spermatogenesis: The commitment to meiosis. Physiol Rev 2016; 96(1): 1-17.
[] [PMID: 26537427]
Chen H, Mruk D, Xiao X, Cheng CY. Human spermatogenesis and its regulation. In: Winters SJ, Huhtaniemi IT, Eds. Male Hypogonadism. Germany: Springer 2017; pp. 49-72.
O'Donnell L. Mechanisms of spermiogenesis and spermiation and how they are disturbed Spermatogenesis 2015; 4(2): e979623-e.
Shupe J, Cheng J, Puri P, Kostereva N, Walker WH. Regulation of Sertoli-germ cell adhesion and sperm release by FSH and nonclassical testosterone signaling. Mol Endocrinol 2011; 25(2): 238-52.
[] [PMID: 21177760]
Walker WH, Cheng J. FSH and testosterone signaling in Sertoli cells. Reproduction 2005; 130(1): 15-28.
[] [PMID: 15985628]
Oduwole OO, Peltoketo H, Huhtaniemi IT. Role of follicle-stimulating hormone in spermatogenesis. Front Endocrinol 2018; 9: 763.
[] [PMID: 30619093]
Zirkin BR, Papadopoulos V. Leydig cells: Formation, function, and regulation. Biol Reprod 2018; 99(1): 101-11.
[] [PMID: 29566165]
Clavijo RI, Hsiao W. Update on male reproductive endocrinology. Transl Androl Urol 2018; 7(Suppl. 3): S367-72.
[] [PMID: 30159243]
Kubota H, Brinster RL. Spermatogonial stem cells. Biol Reprod 2018; 99(1): 52-74.
[] [PMID: 29617903]
Kobayashi H, Nagao K, Nakajima K. Stem cell research for male infertility. Reprod Med Biol 2011; 10(3): 171-4.
[] [PMID: 29699091]
Rombaut C, Mertes H, Heindryckx B, Goossens E. Human in vitro spermatogenesis from pluripotent stem cells: In need of a stepwise differentiation protocol? Mol Hum Reprod 2017; 24(2): 47-54.
Bibi M. Triggers of Spermatogenesis. Sci J Lander College Arts Sci 2019; 12(2): 8.
Hayashi K. In vitro reconstitution of germ cell development. Biol Reprod 2019; 101(3): 567-78.
[] [PMID: 31295346]
West JA, Park I-H, Daley GQ, Geijsen N. In vitro generation of germ cells from murine embryonic stem cells. Nat Protoc 2006; 1(4): 2026-36.
[] [PMID: 17487192]
Yang S, Bo J, Hu H, et al. Derivation of male germ cells from induced pluripotent stem cells in vitro and in reconstituted seminiferous tubules. Cell Prolif 2012; 45(2): 91-100.
[] [PMID: 22324506]
Park TS, Galic Z, Conway AE, et al. Derivation of primordial germ cells from human embryonic and induced pluripotent stem cells is significantly improved by coculture with human fetal gonadal cells. Stem Cells 2009; 27(4): 783-95.
[] [PMID: 19350678]
Panula S, Medrano JV, Kee K, et al. Human germ cell differentiation from fetal- and adult-derived induced pluripotent stem cells. Hum Mol Genet 2011; 20(4): 752-62.
[] [PMID: 21131292]
Sugawa F, Araúzo-Bravo MJ, Yoon J, et al. Human primordial germ cell commitment in vitro associates with a unique PRDM14 expression profile. EMBO J 2015; 34(8): 1009-24.
[] [PMID: 25750208]
Eguizabal C, Montserrat N, Vassena R, et al. Complete meiosis from human induced pluripotent stem cells. Stem Cells 2011; 29(8): 1186-95.
[] [PMID: 21681858]
Medrano JV, Ramathal C, Nguyen HN, Simon C, Reijo Pera RA. Divergent RNA-binding proteins, DAZL and VASA, induce meiotic progression in human germ cells derived in vitro. Stem Cells 2012; 30(3): 441-51.
[] [PMID: 22162380]
Durruthy Durruthy J, Ramathal C, Sukhwani M, et al. Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules. Hum Mol Genet 2014; 23(12): 3071-84.
[] [PMID: 24449759]
Sasaki K, Yokobayashi S, Nakamura T, et al. Robust in vitro induction of human germ cell fate from pluripotent stem cells. Cell Stem Cell 2015; 17(2): 178-94.
[] [PMID: 26189426]
Ramathal C, Durruthy-Durruthy J, Sukhwani M, et al. Fate of iPSCs derived from azoospermic and fertile men following xenotransplantation to murine seminiferous tubules. Cell Rep 2014; 7(4): 1284-97.
[] [PMID: 24794432]
Irie N, Weinberger L, Tang WW, et al. SOX17 is a critical specifier of human primordial germ cell fate. Cell 2015; 160(1-2): 253-68.
[] [PMID: 25543152]
Zhao Y, Ye S, Liang D, et al. In vitro modeling of human germ cell development using pluripotent stem cells. Stem Cell Reports 2018; 10(2): 509-23.
[] [PMID: 29398481]
Wang X, Liao T, Wan C, et al. Efficient generation of human primordial germ cell-like cells from pluripotent stem cells in a methylcellulose-based 3D system at large scale. PeerJ 2019; 6: e6143.
[] [PMID: 30643676]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy