Abstract
Human infertility is a complex disorder at the genetic, molecular, cellular, organ, and hormonal levels. New developing technology based on the generation of human primordial germ cell-like cells (hPGCLCs) from induced pluripotent stem cells (hiPSCs) might improve understanding of early germ cell development (specification, migration, gametogenesis, and epigenetic reconstitutions), as well as offering a solution for infertility and hereditary disorders. In this study, we differentiated hiPSCs with trisomy 21 into hPGCLCs. In vitro-derived germ cells from hiPSCs with Down syndrome (DS) express hPGCLC core circuitry, EOMES, SOX17, and PRDM14 at relatively low levels. TFAP2C and PRDM1 were expressed and remained elevated, whereas NANOS3 and NANOG were downregulated in BMP4-induced hiPSCs with DS. The low level of NANOG and NANOS3 expression might negatively influence hPGCLC generation in DS hiPSCs. We suggest that DS hPGCLCs could be a suitable model for studying human early germ cell development, the epigenetic and molecular mechanisms of PGC specification and formation, as well as related infertility disorders, such as azoospermia and teratozoospermia.
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References
Abdyyev VK, Sant DW, Kiseleva EV, Spangenberg VE, Kolomiets OL, Andrade NS, Dashinimaev EB, Vorotelyak EA, Vasiliev AV (2020) In vitro derived female hPGCLCs are unable to complete meiosis in embryoid bodies. Exp Cell Res. https://doi.org/10.1016/j.yexcr.2020.112358
Aghajanova L, Popwell JM, Chetkowski RJ, Herndon CN (2015) Birth of a healthy child after preimplantation genetic screening of embryos from sperm of a man with non-mosaic Down syndrome. JARG 32(9):1409–1413. https://doi.org/10.1007/s10815-015-0525-z
Angeles Julaton VT, Reijo Pera RA (2011) NANOS3 function in human germ cell development. Hum Mol Genet 20(11):2238–2250. https://doi.org/10.1093/hmg/ddr114
Bachmann-Waldmann C, Jentsch S, Tobler H, Müller F (2004) Chromatin diminution leads to rapid evolutionary changes in the organization of the germ line genomes of the parasitic nematodes A. suum and P. univalens’. MBP. https://doi.org/10.1016/j.molbiopara.2003.11.001.
Bovicelli L, Orsini LF, Rizzo N, Montacuti V, Bacchetta M (1982) Reproduction in Down syndrome. Obstet Gynecol 59(6): 13S-17S. https://europepmc.org/article/med/6211644 (Accessed: 27 May 2021).
Chew G, Hutson JM (2004) Incidence of cryptorchidism and ascending testes in Trisomy 21: a 10 year retrospective review. Pediatr Surg Int 20(10):744–747. https://doi.org/10.1007/s00383-004-1290-8
Deshpande G, Calhoun G, Yanowitz JL, Schedl PD (1999) Novel functions of nanos in downregulating mitosis and transcription during the development of the Drosophila germline. Cell 99(3):271–281. https://doi.org/10.1016/S0092-8674(00)81658-X
Deutsch S, Lyle R, Dermitzakis ET, Attar H, Subrahmanyan L, Gehrig C, Parand L, Gagnebin M, Rougemont J, Jongeneel CV, Antonarakis SE (2005) Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes. Hum Mol Genet. https://doi.org/10.1093/hmg/ddi404
Eyman RK, Call TL, White JF (1991) Life expectancy of persons with Down syndrome. Am J Ment Retard 95(6):603–612
Fernandes MG, Bialecka M, Salvatori DCF, De Sousa C, Lopes SM (2018) Characterization of migratory primordial germ cells in the aorta-gonad-mesonephros of a 4.5-week-old human embryo: a toolbox to evaluate in vitro early gametogenesis. MHR 24(5):233–243. https://doi.org/10.1093/molehr/gay011
Goday C, Pimpinelli S (1993) The occurrence, role and evolution of chromatin diminution in nematodes. Parasitol Today. https://doi.org/10.1016/0169-4758(93)90229-9
Gribouval L, Sourdaine P, Lareyre JJ, Bellaiche J, Le Gac F, Mazan S, Guiardiere C, Auvray P, Gautier A (2018) The nanos1 gene was duplicated in early Vertebrates and the two paralogs show different gonadal expression profiles in a shark. Sci Rep 8(1):1–14. https://doi.org/10.1038/s41598-018-24643-1
Guo G, Meyenn FV, Rostovskaya M, Clarke J, Dietmann S, Baker D, Sahakyan A, Myers S, Bertone P, Reik W, Plath K, Smith A (2018) Epigenetic resetting of human pluripotency. Dev. https://doi.org/10.1242/dev.166397
Højager B, Peters H, Byskov AG, Faber M (1978) Follicular development in ovaries of children with down’s syndrome. Acta Pædiatr. https://doi.org/10.1111/j.1651-2227.1978.tb17815.x
Hsiang YHH, Berkovitz GD, Bland GL, Migeon CJ, Warren AC (1987) Gonadal function in patients with Down syndrome. Am J Med Genet 27(2):449–458. https://doi.org/10.1002/ajmg.1320270223
Irie N, Weinberger L, Tang WWC, Kobayashi T, Viukov S, Manor YS, Dietmann S, Hanna JH, Surani MA (2015) SOX17 is a critical specifier of human primordial germ cell fate. Cell the Authors 160(1–2):253–268. https://doi.org/10.1016/j.cell.2014.12.013
Jazayeri O, Gorjizadeh N (2020) A male Down syndrome with two normal boys: cytogenetic, paternity and andrological investigations. Andrologia. https://doi.org/10.1111/and.13521
Kaushal M, Baxi A, Kadi P, Karandae J, Baxi D (2010) Woman with Down syndrome delivered a normal child. J Infertil Fetal Med Int. https://doi.org/10.5005/jp-journals-10016-1008
Kobayashi T, Surani MA (2018) On the origin of the human germline. Dev 145(16):2–5. https://doi.org/10.1242/dev.150433
Kojima Y, Sasaki K, Yokobayashi S, Sakai Y, Nakamura T, Yabuta Y, Nakaki F, Nagaoka S, Woltjen K, Hotta A, Yamamoto T, Saitou M (2017) Evolutionarily distinctive transcriptional and signaling programs drive human germ cell lineage specification from pluripotent stem cells. Cell Stem Cell Cell Press 21(4):517-532.e5. https://doi.org/10.1016/j.stem.2017.09.005
Kuliev A, Verlinsky Y (2004) Meiotic and mitotic nondisjunction: lessons from preimplantation genetic diagnosis. Hum Reprod Update. https://doi.org/10.1093/humupd/dmh036
Liu X, Nefzger CM, Rossello FJ, Chen J, Knaupp AS, Firas J, Ford E, Pflueger J, Paynter JM, Chy HS, Huang C, Mishra K, Hodgson-Garms M, Jansz N, Williams SM, Blewitt ME, Nilsson SK, Schittenhelm RB, Laslett AL, Lister R, Polo JM (2017) Comprehensive characterization of distinct states of human naive pluripotency generated by reprogramming. Nat Methods. https://doi.org/10.1038/nmeth.4436
Miki M, Ohtake N, Hasumi M, Ohi M, Moriyama S (1999) Seminoma associated with bilateral cryptorchidism in Down’s syndrome: a case report. Int J Urol 6(7):377–380. https://doi.org/10.1046/j.1442-2042.1999.00078.x
Müller F, Tobler H (2000) Chromatin diminution in the parasitic nematodes Ascaris suum and Parascaris univalens. Int J Parasitol. https://doi.org/10.1016/S0020-7519(99)00199-X
Müller F, Bernard V, Tobler H (1996) Chromatin diminution in nematodes. BioEssays. https://doi.org/10.1002/bies.950180209
Orthmann Bless D, Hofmann V (2020) Pregnancies and births in women with Down syndrome–an analysis based on the medical statistics of swiss hospitals. J Intellect Dev Disabil. https://doi.org/10.3109/13668250.2020.1767767
Panula S, Reda A, Stukenborg J-BB, Ramathal C, Sukhwani M, Albalushi H, Edsgärd D, Nakamura M, Söder O, Orwig KE, Yamanaka S, Reijo Pera RA, Hovatta O (2016) ‘Over expression of NANOS3 and DAZL in human embryonic stem cells. PLoS ONE 11(10):e0165268. https://doi.org/10.1371/journal.pone.0165268
Papavassiliou P, Charalsawadi C, Rafferty K, Jackson-Cook C (2015) Mosaicism for trisomy 21: a review. Am J Med Genet Part A. https://doi.org/10.1002/ajmg.a.36861
Perrett RM, Turnpenny L, Eckert JJ, O’Shea M, Sonne SB, Cameron IT, Wilson DI, Rajpert-De Meyts E, Hanley N, a, (2008) ‘The early human germ cell lineage does not express SOX2 during in vivo development or upon in vitro culture. Biol Reprod 78(5):852–858. https://doi.org/10.1095/biolreprod.107.066175
Pradhan M, Dalal A, Khan F, Agrawal S (2006) Fertility in men with Down syndrome: a case report. Fertil Steril 86(6):1765.e1-1765.e3. https://doi.org/10.1016/j.fertnstert.2006.03.071
Prandini P, Deutsch S, Lyle R, Gagnebin M, Vivier CD, Delorenzi M, Gehrig C, Descombes P, Sherman S, Bricarelli FD, Baldo C, Novelli A, Dallapiccola B, Antonarakis SE (2007) Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am J Hum Genet 81(2):252–263. https://doi.org/10.1086/519248
Shobha Rani A, Jyothi A, Reddy PP, Reddy OS (1990) Reproduction in down’s syndrome. Int J Gynecol Obstet. https://doi.org/10.1016/0020-7292(90)90187-P
Sugawa F, Araúzo-Bravo MJ, Yoon J, Kim K-P, Aramaki S, Wu G, Stehling M, Psathaki OE, Hübner K, Schöler HR (2015) Human primordial germ cell commitment in vitro associates with a unique PRDM14 expression profile. Embo J 34(8):1009–1024. https://doi.org/10.15252/embj.201488049
Sybirna A, Tang WWC, Pierson Smela M, Dietmann S, Gruhn WH, Brosh R, Surani MA (2020) ‘A critical role of PRDM14 in human primordial germ cell fate revealed by inducible degrons. Nat Commun. https://doi.org/10.1038/s41467-020-15042-0
Welling M, Chen H-H, Munoz J, Musheev MU, Kester L, Junker JP, Mischerikow N, Arbab M, Kuijk E, Silberstein L, Kharchenko PV, Geens M, Niehrs C, van de Velde H, van Oudenaarden A, Heck AJ, Geijsen N (2015) DAZL regulates Tet1 translation in murine embryonic stem cells. EMBO Rep 16(7):791–802. https://doi.org/10.15252/embr.201540538
Yamaji M, Tanaka T, Shigeta M, Chuma S, Saga Y, Saitou M (2010) Functional reconstruction of NANOS3 expression in the germ cell lineage by a novel transgenic reporter reveals distinct subcellular localizations of NANOS3. Reprod 139(2):381–393. https://doi.org/10.1530/REP-09-0373
Acknowledgements
We thank MBiol student Nelli Arakelyan for her helpful contribution in running gel electrophoresis.
Funding
The work was performed according to the IDB RAS No. 0088-2021-0016 Government basic research program. The research on gene expression analysis was supported by grant no. 075-15-2019-1789 from the Ministry of Science and Higher Education of the Russian Federation, allocated to the Center for Precision Genome Editing and Genetic Technologies for Biomedicine. Also, we thank the Core Centrum of the Institute of Developmental Biology RAS for the opportunity to work on the equipment of the center.
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V.K.A.: investigation, writing the original draft, conceptualization. N.O.D.: formal analysis, validation. E.B.D.: conceptualization. E.A.V.: supervision, editing the manuscript. A.V.V.: supervision, editing the manuscript, funding acquisition.
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Abdyyev, V.K., Dashenkova, N.O., Dashinimaev, E.B. et al. NANOS3 downregulation in Down syndrome hiPSCs during primordial germ cell-like cell differentiation. Histochem Cell Biol 157, 83–91 (2022). https://doi.org/10.1007/s00418-021-02040-6
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DOI: https://doi.org/10.1007/s00418-021-02040-6