The reciprocal relationship between primordial germ cells and pluripotent stem cells

Pirouz, Mehdi; Klimke, Ansgar; Kessel, Michael

doi:10.1007/s00109-012-0912-1

Cited by 13 publications

(19 citation statements)

References 88 publications

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“…Evidence for this is provided in part by significant upregulation of premeiotic germ cell markers NANOS3, VASA and DPPA3 upon BMP4 differentiation and a greater potential to enter meiosis compared with the OSKM counterparts. It is worth nothing that PGC culture in vitro under proliferative conditions can result in derivation of pluripotent embryonic germ cell lines capable of differentiating to somatic and germline progeny cells; moreover, several studies have provided evidence of extensive similarity between ESCs and early germ cells (11,41). In contrast, the ontogeny of mouse iPSCs versus mouse PGCs is a more distant one than in humans (3).…”

Section: Discussionmentioning

confidence: 99%

Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules

Durruthy

Ramathal

Sukhwani

et al. 2014

Human Molecular Genetics

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Studies of human germ cell development are limited in large part by inaccessibility of germ cells during development. Moreover, although several studies have reported differentiation of mouse and human germ cells from pluripotent stem cells (PSCs) in vitro, differentiation of human germ cells from PSCs in vivo has not been reported. Here, we tested whether mRNA reprogramming in combination with xeno-transplantation may provide a viable system to probe the genetics of human germ cell development via use of induced pluripotent stem cells (iPSCs). For this purpose, we derived integration-free iPSCs via mRNA-based reprogramming with OCT3/4, SOX2, KLF4 and cMYC alone (OSKM) or in combination with the germ cell-specific mRNA, VASA (OSKMV). All iPSC lines met classic criteria of pluripotency. Moreover, global gene expression profiling did not distinguish large differences between undifferentiated OSKM and OSKMV iPSCs; however, some differences were observed in expression of pluripotency factors and germ cell-specific genes, and in epigenetic profiles and in vitro differentiation studies. In contrast, transplantation of undifferentiated iPSCs directly into the seminiferous tubules of germ cell-depleted immunodeficient mice revealed divergent fates of iPSCs produced with different factors. Transplantation resulted in morphologically and immunohistochemically recognizable germ cells in vivo, particularly in the case of OSKMV cells. Significantly, OSKMV cells also did not form tumors while OSKM cells that remained outside the seminiferous tubule proliferated extensively and formed tumors. Results indicate that mRNA reprogramming in combination with transplantation may contribute to tools for genetic analysis of human germ cell development.

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Section: Discussionmentioning

confidence: 99%

Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules

Durruthy

Ramathal

Sukhwani

et al. 2014

Human Molecular Genetics

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“…Interestingly some of the gonadal cells in Dmrt1 mutants, as well as in animals heterozygous for Tfap2c and Nanos3 also fail to downregulate pluripotency markers after arrival in the genital ridge in the 129 genetic background (Krentz et al 2013, Schemmer et al 2013. In these mutants, the persistence of Nanog and Oct3/4 as well as other PGC and pluripotency marker genes like Dnd1, Prdm14, Lin28, cKit and Dppa3 counteracts apoptosis leading to rapid development of a germ cell tumor equivalent to a type I GCT, an early childhood tumor (Kehler et al 2004, Western 2009, Pirouz et al 2012. These data in mice suggest that interference with genes involved in downregulation of the pluripotency genes after arrival in the genital ridge is a critical (and error-prone) step.…”

Section: Type I and Type Ii Gcts: Results Of A Flawed Licensingmentioning

confidence: 99%

Elucidating human male germ cell development by studying germ cell cancer

Nettersheim¹,

Jostes²,

Schneider³

et al. 2016

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“…22 The resulting embryonic germ cells are indistinguishable from ESCs. 23 We have recently demonstrated the absolute requirement of PGCs for the multi-functional protein Mad2l2, which influences their cell cycle and epigenetic reprogramming. 24 The Mad2l2 protein is distantly related to the spindle checkpoint regulator Mad2 (Mad2l1) and consists mostly of a single domain, the HORMA domain that is known to interact with many proteins.…”

Section: Introductionmentioning

confidence: 99%

Destabilization of pluripotency in the absence of Mad2l2

et al. 2015

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The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2¡/¡ ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm. However, they could be stably propagated using small molecule inhibitors of MAPK signaling. Several components of the MAPK cascade were up-or downregulated even in undifferentiated Mad2l2 ¡/¡ ESCs. Global levels of repressive histone H3 variants were increased in mutant ESCs, and the epigenetic signatures on pluripotency-, primitive endoderm-, and MAPK-related loci differed. Thus, H3K9me2 repressed the Nanog promoter, while the promoter of Gata4 lost H3K27me3 and became de-repressed in LIF/serum condition. Promoters associated with genes involved in MAPK signaling also showed misregulation of these histone marks. Such epigenetic modifications could be indirect consequences of mutating Mad2l2. However, our previous observations suggested the histone methyltransferases as direct (G9a) or indirect (Ezh2) targets of Mad2l2. In effect, the intricate balance necessary for pluripotency becomes perturbed in the absence of Mad2l2.

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The reciprocal relationship between primordial germ cells and pluripotent stem cells

Cited by 13 publications

References 88 publications

Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules

Fate of induced pluripotent stem cells following transplantation to murine seminiferous tubules

Elucidating human male germ cell development by studying germ cell cancer

Destabilization of pluripotency in the absence of Mad2l2

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