Intrinsic factors and the embryonic environment influence the formation of extragonadal teratomas during gestationReportar como inadecuado




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BMC Developmental Biology

, 15:35

Early development

Abstract

BackgroundPluripotent cells are present in early embryos until the levels of the pluripotency regulator Oct4 drop at the beginning of somitogenesis. Elevating Oct4 levels in explanted post-pluripotent cells in vitro restores their pluripotency. Cultured pluripotent cells can participate in normal development when introduced into host embryos up to the end of gastrulation. In contrast, pluripotent cells efficiently seed malignant teratocarcinomas in adult animals. In humans, extragonadal teratomas and teratocarcinomas are most frequently found in the sacrococcygeal region of neonates, suggesting that these tumours originate from cells in the posterior of the embryo that either reactivate or fail to switch off their pluripotent status. However, experimental models for the persistence or reactivation of pluripotency during embryonic development are lacking.

MethodsWe manually injected embryonic stem cells into conceptuses at E9.5 to test whether the presence of pluripotent cells at this stage correlates with teratocarcinoma formation. We then examined the effects of reactivating embryonic Oct4 expression ubiquitously or in combination with Nanog within the primitive streak PS-tail bud TB using a transgenic mouse line and embryo chimeras carrying a PS-TB-specific heterologous gene expression cassette respectively.

ResultsHere, we show that pluripotent cells seed teratomas in post-gastrulation embryos. However, at these stages, induced ubiquitous expression of Oct4 does not lead to restoration of pluripotency indicated by Nanog expression and tumour formation in utero, but instead causes a severe phenotype in the extending anteroposterior axis. Use of a more restricted TBra promoter transgenic system enabling inducible ectopic expression of Oct4 and Nanog specifically in the posteriorly-located primitive streak PS and tail bud TB led to similar axial malformations to those induced by Oct4 alone. These cells underwent induction of pluripotency marker expression in Epiblast Stem Cell EpiSC explants derived from somitogenesis-stage embryos, but no teratocarcinoma formation was observed in vivo.

ConclusionsOur findings show that although pluripotent cells with teratocarcinogenic potential can be produced in vitro by the overexpression of pluripotency regulators in explanted somitogenesis-stage somatic cells, the in vivo induction of these genes does not yield tumours. This suggests a restrictive regulatory role of the embryonic microenvironment in the induction of pluripotency.

KeywordsExtragonadal teratoma Pluripotency Oct4 Nanog Brachyury Inducible expression AbbreviationsESEmbryonic stem

EpiSCEpiblast stem cell

ECEmbryonal carcinoma

PGCsPrimordial germ cells

TBTail bud

CNHChordoneural hinge

NMNeuromesodermal

DoxDoxycycline

TRETetracycline responsive element

PSPrimitive streak

Constantinos Economou and Anestis Tsakiridis contributed equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1186-s12861-015-0084-7 contains supplementary material, which is available to authorized users.

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Autor: Constantinos Economou - Anestis Tsakiridis - Filip J. Wymeersch - Sabrina Gordon-Keylock - Robert E Dewhurst - Dawn Fisher

Fuente: https://link.springer.com/







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