Mechanisms of pluripotency and epigenetic reprogramming in primordial germ cells: lessons for the conversion of other cell types into the stem cell lineage

Primordial germ cells (PGCs) provide an excellent tool to better understand ancestor?descendent relationships as well as the efficiency and molecular mechanisms governing pluripotency in the reprogramming of somatic cells, since the latter type of cells have a relatively lower efficiency of conversion to pluripotent cells. This kind of comparison has gained credence from the commonalities regarding the expression of key transcription factors such as octamer-binding transcriptionhttp://en.wikipedia.org/wiki/Transcription_factor factor-4 (Oct3/4), SRY-related HMG box (Sox2), myelocytomatosis (c-Myc), and Nanog, as well as redundancy in terms of Kruppel-like factor 2 (Klf2), Kruppel-like factor 5 (Klf5), estrogen-related receptor beta (Esrrb), and estrogen-related receptor gamma (Esrrg) compensating for the absence of Kruppel-like factor 4 (Klf4). However, the exogenous addition of any one of these factors was found to be important, thereby implying that the expression level is important. L-Myelocytomatosis (L-myc) was shown to improve reprogramming efficiency without affecting tumorigenic potential. Molecular aspects of epigenetic reprogramming during the acquisition of pluripotency, as well as tumorigenic potential, have also been discussed, thus providing an understanding of the factors that can improve the former without increasing the possibility of neoplastic transformation. An improved understanding of the molecular events would pave the way for the development and use of endogenous biomolecules as well as currently available chemical reprogrammers for improving the efficiency of conversion of PGCs into cells of the stem cell lineage. Such chemicals, when adequately tested, can possibly be an alternative to viral vectors, since the introduced transgenes can become oncogenic.

Anahtar Kelimeler:

Primordial germ cells, stem cells, chemical/genetic reprogramming, pluripotency, transcription factors, epigenetic, induced pluripotent stem cells, embryonic germ cells, embryonic stem cells, epiblast stem cells

Mechanisms of pluripotency and epigenetic reprogramming in primordial germ cells: lessons for the conversion of other cell types into the stem cell lineage

Keywords:

Primordial germ cells, stem cells, chemical/genetic reprogramming, pluripotency, transcription factors, epigenetic, induced pluripotent stem cells, embryonic germ cells, embryonic stem cells, epiblast stem cells,

PDF

___

Apostolou E, Ferrari F, Walsh RM, Bar-Nur O, Stadtfeld M, Cheloufi S, Stuart HT, Polo JM, Ohsumi TK, Borowsky ML et al. (2013). Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. Cell Stem Cell 12: 699–712.
Bao S, Leitch HG, Gillich A, Nichols J, Tang F, Kim S, Lee C, Zwaka T, Li X, Surani MA (2012). The germ cell determinant Blimp1 is not required for derivation of pluripotent stem cells. Cell Stem Cell 11: 110–117.
Cheng L, Gearing DP, White LS, Compton DL, Schooley K, Donovan PJ (1994). Role of leukemia inhibitory factor and its receptor in mouse primordial germ cell growth. Development 120: 3145–3153.
De Felici M, Farini D, Dolci S (2009). In or out stemness: comparing growth factor signalling in mouse embryonic stem cells and primordial germ cells. Curr Stem Cell Res Ther 4: 87–97.
De Los Angeles A, Daley GQ (2013). A chemical logic for reprogramming to pluripotency. Cell Res 23: 1337–1338.
Dolci S, Pesce M, De Felici M (1993). Combined action of stem cell factor, leukemia inhibitory factor, and cAMP on in vitro proliferation of mouse primordial germ cells. Mol Reprod Dev 35: 134–139.
Donovan PJ (1994). Growth factor regulation of mouse primordial germ cell development. Curr Top Dev Biol 29: 189–225.
Durcova-Hills G, Adams IR, Barton SC, Surani MA, McLaren A (2006). The role of exogenous fibroblast growth factor-2 on the reprogramming of primordial germ cells into pluripotent stem cells. Stem Cells 24: 1441–1449.
Durcova-Hills G, Tang F, Doody G, Tooze R, Surani MA (2008). Reprogramming primordial germ cells into pluripotent stem cells. PLoS One 3: e3531.
Farini D, Scaldaferri ML, Iona S, La Sala G, De Felici M (2005). Growth factors sustain primordial germ cell survival, proliferation and entering into meiosis in the absence of somatic cells. Dev Biol 285: 49–56.
Ferrari F, Apostolou E, Park PJ, Hochedlinger K (2014). Rearranging the chromatin for pluripotency. Cell Cycle 13: 167–168.
Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, Marques CJ, Andrews S, Reik W (2011). Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473: 398–402.
Ficz G, Hore TA, Santos F, Lee HJ, Dean W, Arand J, Krueger F, Oxley D, Paul YL, Walter J et al. (2013). FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell 13: 351–359.
Ginsburg M, Snow MHL, McLaren A (1990). Primordial germ cells in the mouse embryo during gastrulation. Development 110: 521–528.
Grabole N, Tischler J, Hackett JA, Kim S, Tang F, Leitch HG, Magnşsdóttir E, Surani MA (2013). Prdm14 promotes germline fate and naive pluripotency by repressing FGF signalling and DNA methylation. EMBO Rep 14: 629–637.
Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA (2013). Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethyl cytosine. Science 339: 448–452.
Hackett JA, Zylicz JJ, Surani MA (2012). Parallel mechanisms of epigenetic reprogramming in the germline. Trends Genet 28: 164–174.
Hanna JH, Saha K, Jaenisch R (2010). Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143: 508–525.
Hatano SY, Tada M, Kimura H, Yamaguchi S, Kono T, Nakano T, Suemori H, Nakatsuji N, Tada T (2005). Pluripotential competence of cells associated with Nanog activity. Mech Dev 122: 67–79.
Hayashi K, Surani MA (2009). Self-renewing epiblast stem cells exhibit continual delineation of germ cells with epigenetic reprogramming in vitro. Development 136: 3549–3556.
Hemberger M, Dean W, Reik W (2009). Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington’s canal. Nat Rev Mol Cell Biol 10: 526–537.
Ho R, Papp B, Hoffman JA, Merrill BJ, Plath K (2013). Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins. Cell Rep 3: 2113–2126.
Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K et al. (2013). Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341: 651–654.
Hu WT, Yan QY, Fang Y, Qiu ZD, Zhang SM (2014).Transient folate deprivation in combination with small-molecule compounds facilitates the generation of somatic cell-derived pluripotent stem cells in mice. J Huazhong Univ Sci Technolog Med Sci 34: 151–156.
Ieda M, Fu JD, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau BG, Srivastava D (2010). Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142: 375–386.
Kidder BL (2014). Generation of induced pluripotent stem cells using chemical inhibition and three transcription factors. Methods Mol Biol 1150: 227–236.
Kimura T, Kaga Y, Sekita Y, Fujikawa K, Nakatani T, Odamoto M, Funaki S, Ikawa M, Abe K, Nakano T (2015). Pluripotent stem cells derived from mouse primordial germ cells by small molecule compounds. Stem Cells 33: 45–55.
Kimura T, Nakano T (2011). Induction of pluripotency in primordial germ cells. Histol Histopathol 26: 643–650.
Kobayashi H, Sakurai T, Miura F, Imai M, Mochiduki K, Yanagisawa E, Sakashita A, Wakai T, Suzuki Y, Ito T et al. (2013). High- resolution DNA methylome analysis of primordial germ cells identifies gender-specific reprogramming in mice. Genome Res 23: 616–627.
Kurimoto K, Yabuto Y, Ohinato Y, Shigeta M, Yamanaka K, Saitou M (2008a). Complex genome-wide transcription dynamics orchestrated by Blimp-1 for the specification of the germ cell lineage in mice. Gene Dev 22: 1617–1635.
Kurimoto K, Yamaji M, Seki Y, Saitou M (2008b). Specification of the germ cell lineage in mice: a process orchestrated by the PR-domain proteins, Blimp1 and Prdm14. Cell Cycle 7: 3514– 3518.
Lee HJ, Hore TA, Reik W (2014). Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell 14: 710–719.
Leitch HG, Blair K, Mansfield W, Ayetey H, Humphreys P, Nichols J, Surani MA, Smith A (2010). Embryonic germ cells from mice and rats exhibit properties consistent with a generic pluripotent ground state. Development 137: 2279–2287.
Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T, Grabole N, Mansfield W, Nashun B, Knezovich JG, Smith A et al. (2013a). Naive pluripotency is associated with global DNA hypomethylation. Nat Struct Mol Biol 20: 311–316.
Leitch HG, Nichols J, Humphreys P, Mulas C, Martello G, Lee C, Jones K, Surani MA, Smith A (2013b). Rebuilding pluripotency from primordial germ cells. Stem Cell Reports 1: 66–78.
Li H, Collado M, Villasante A, Strati K, Ortega S, Cañamero M, Blasco MA, Serrano M (2009). The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 460: 1136–1139.
Li XH, Cong HC, Wang Z, Wu CF, Cao YL (2002). Isolation and culture of human pluripotent embryonic germ cells. Shi Yan Sheng Wu Xue Bao 35: 142–146 (article in Chinese with English abstract).
Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, Ge J, Liu C, Zhang W, Zhang X et al. (2011). Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res 21: 196–204.
Mansour AA, Gafni O, Weinberger L, Zviran A, Ayyash M, Rais Y, Krupalnik V, Zerbib M, Amann-Zalcenstein D, Maza I et al. (2012). The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 488: 409–413.
Masuda S, Wu J, Hishida T, Pandian GN, Sugiyama H, Izpisua Belmonte JC (2013). Chemically induced pluripotent stem cells (CiPSCs): a transgene-free approach. J Mol Cell Biol 5: 354–355.
Matsui Y, Zsebo K, Hogan BL (1992). Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70: 841–847.
Nagamatsu G, Kosaka T, Saito S, Honda H, Takubo K, Kinoshita T, Akiyama H, Sudo T, Horimoto K, Oya M et al. (2013). Induction of pluripotent stem cells from primordial germ cells by single reprogramming factors. Stem Cells 31: 479–487.
Nagamatsu G, Kosaka T, Saito S, Takubo K, Akiyama H, Sudo T, Horimoto K, Oya M, Suda T (2012a). Tracing the conversion process from primordial germ cells to pluripotent stem cells in mice. Biol Reprod 86: 182.
Nagamatsu G, Saito S, Kosaka T, Takubo K, Kinoshita T, Oya M, Horimoto K, Suda T (2012b). Optimal ratio of transcription factors for somatic cell reprogramming. J Biol Chem 287: 36273–36282.
Nagamatsu G, Suda T (2013). Conversion of primordial germ cells to pluripotent stem cells: methods for cell tracking and culture conditions. Methods Mol Biol 1052:49–56.
Nakagawa M, Takizawa N, Narita M, Ichisaka T, Yamanaka S (2010). Promotion of direct reprogramming by transformation- deficient Myc. P Natl Acad Sci USA 107: 14152–14157.
Ohinata Y, Payer B, O’Carroll D, Ancelin K, Ono Y, Sano M, Barton SC, Obukhanych T, Nussenzweig M, Tarakhovsky A et al. (2005). Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436: 207–213.
Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, Hong H, Nakagawa M, Tanabe K, Tezuka K et al. (2011). A more efficient method to generate integration-free human iPS cells. Nat Methods 8: 409–412.
Pashai N, Hao H, All A, Gupta S, Chaerkady R, De Los Angeles A, Gearhart JD, Kerr CL (2012). Genome-wide profiling of pluripotent cells reveals a unique molecular signature of human embryonic germ cells. PLoS One 7: e39088.
Pesce M, Farrace MG, Piacentini M, Dolci S, De Felici M (1993). Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis). Development 118: 1089–1094.
Resnick JL, Ortiz M, Keller JR, Donovan PJ (1998). Role of fibroblast growth factors and their receptors in mouse primordial germ cell growth. Biol Reprod 59: 1224–1229.
Seisenberger S, Andrews S, Krueger F, Arand J, Walter J, Santos F, Popp C, Thienpont B, Dean W, Reik W (2012). The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell 48: 849–862.
Seisenberger S, Peat JR, Reik W (2013). Conceptual links between DNA methylation reprogramming in the early embryo and primordial germ cells. Curr Opin Cell Biol 25: 281–288.
Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, Blumenthal PD, Huggins GR, Gearhart JD (1998). Derivation of pluripotent stem cells from cultured human primordial germ cells. P Natl Acad Sci USA 95: 13726–13731 (erratum in P Natl Acad Sci USA 1999; 96: 1162).
Sharova LV, Sharov AA, Piao Y, Shaik N, Sullivan T, Stewart CL, Hogan BL, Ko MS (2007). Global gene expression profiling reveals similarities and differences among mouse pluripotent stem cells of different origins and strains. Dev Biol 307: 446–459.
Shi Y, Desponts C, Do JT, Hahm HS, Schöler HR, Ding S (2008). Induction of pluripotent stem cells from mouse embryonic fibroblasts by Oct4 and Klf4 with small-molecule compounds. Cell Stem Cell 3: 568–574.
Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663–676.
Vaskova EA, Stekleneva AE, Medvedev SP, Zakian SM (2013). “Epigenetic memory” phenomenon in induced pluripotent stem cells. Acta Naturae 5: 15–21.
Watanabe S, Umehara H, Murayama K, Okabe M, Kimura T, Nakano T (2006). Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells. Oncogene 25: 2697–2707.
Wei X, Chen Y, Xu Y, Zhan Y, Zhang R, Wang M, Hua Q, Gu H, Nan F, Xie X (2014). Small molecule compound induces chromatin de-condensation and facilitates induced pluripotent stem cell generation. J Mol Cell Biol (in press).
Wong TT, Collodi P (2013). Effects of specific and prolonged expression of zebrafish growth factors, Fgf2 and Lif in primordial germ cells in vivo. Biochem Biophys Res Commun 430: 347–351.
Wossidlo M, Nakamura T, Lepikhov K, Marques CJ, Zakhartchenko V, Boiani M, Arand J, Nakano T, Reik W, Walter J (2011). 5-Hydroxymethylcytosine in the mammalian zygote is linked with epigenetic reprogramming. Nat Commun 2: 241.
Wu J, Tzanakakis ES (2013). Deconstructing stem cell population heterogeneity: single-cell analysis and modeling approaches (2013). Biotechnol Adv 31: 1047–1062.
Yabuto Y, Kurimoto K, Ohinata Y, Seki Y, Saitou M (2006). Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biol Reprod 75: 705–716.
Yamaji M, Seki Y, Kurimoto K, Yabuta Y, Yuasa M, Shigeta M, Yamanaka K, Ohinata Y, Saitou M (2008). Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat Genet 40: 1016–1022.
Yamano N, Kimura T, Watanabe-Kushima S, Shinohara T, Nakano T (2010). Metastable primordial germ cell-like state induced from mouse embryonic stem cells by Akt activation. Biochem Biophys Res Commun 392: 311–316.
Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A (2008). The ground state of embryonic stem cell self-renewal. Nature 453: 519–523.
Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA (2009). Human-induced pluripotent stem cells free of vector and transgene sequences. Science 324: 797–801.