Trophoblast organoids as a model for maternal–fetal interactions during human placentation

Turco, Margherita Y.; Gardner, Lucy; Kay, Richard G.; Hamilton, Russell S.; Prater, Malwina; Hollinshead, Michael; McWhinnie, Alasdair; Esposito, Laura; Fernando, Ridma C.; Skelton, Helen E.; Reimann, Frank; Gribble, Fiona M.; Sharkey, Andrew; Marsh, Steven G.E.; O’Rahilly, Stephen; Hemberger, Myriam; Burton, Graham J.; Moffett, Ashley

doi:10.1038/s41586-018-0753-3

Cited by 509 publications

(588 citation statements)

References 36 publications

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“…Recent optimization of culture conditions for primary human first trimester trophoblasts has led to the development of in vitro trophoblast stem cell lines [28][29][30] . Okae et al 29 defined a TSC medium capable of supporting continued proliferation of primary human cytotrophoblasts and blastocyst-derived trophoblasts when cultured on a collagen type IV matrix.…”

Section: Introduction (Main Text Not Including Abstract Methods Refmentioning

confidence: 99%

“…The organoids were maintained for up to five passages and upon removal of R-spondin and CHIR99021 from the culture media, trophoblastic outgrowths formed that were HLA-G positive, a hallmark of human EVTs. A trophoblast organoid model was also developed by Turco et al 30 , where following enzymatic digestion of 6-9 week human placental tissue, cell clusters were embedded into Matrigel. Similar to the trophoblast organoids generated by Haider et al 28 , these organoids formed mononuclear cells on the periphery with syncytia and lacuna structures within the center.…”

Section: Introduction (Main Text Not Including Abstract Methods Refmentioning

confidence: 99%

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Derivation of macaque trophoblast stem cells

Schmidt

Meyer

Wiepz

et al. 2020

Preprint

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200 words max) Nonhuman primates are excellent models for studying human placentation as experimental manipulations in vitro can be translated to in vivo pregnancy. Our objective was to develop macaque trophoblast stem cells (TSC) as an in vitro platform for future assessment of primate trophoblast development and function. Macaque TSC lines were generated by isolating first trimester placental villous cytotrophoblasts followed by culture in TSC medium to "reprogram" the cells to a proliferative state. TSCs grew as mononuclear colonies, whereas upon induction of syncytiotrophoblast (ST) differentiation multinuclear structures appeared, indicative of syncytium formation. Chorionic gonadotropin secretion was >4,000-fold higher in ST culture media compared to TSC media. Characteristic trophoblast hallmarks were defined in TSCs and ST including expression of C19MC miRNAs and macaque placental nonclassical MHC class I molecule, Mamu-AG. TSC differentiation to extravillous trophoblasts (EVTs) with or without the ALK-5 inhibitor A83-01 resulted in differing morphologies but similar expression of Mamu-AG and CD56 as assessed by flow cytometry, hence further refinement of relevant EVT markers is needed. Our preliminary characterization of macaque TSCs suggests that these cells represent a proliferative, self-renewing TSC population capable of differentiating to STs in vitro thereby establishing an experimental model of primate placentation.

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Section: Introduction (Main Text Not Including Abstract Methods Refmentioning

confidence: 99%

Section: Introduction (Main Text Not Including Abstract Methods Refmentioning

confidence: 99%

Derivation of macaque trophoblast stem cells

Schmidt

Meyer

Wiepz

et al. 2020

Preprint

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show abstract

“…These improvements will further increase the placental volume of the embryo during post‐implantation . Under 3D in vitro culture conditions, ESCs with self‐assembling properties can develop into natural embryos‐like structures . For example, Harrison et al found that in 3D matrigel, after 96 hours, ESCs can self‐assemble into a cylindrical structure similar to a natural mouse embryo (Figure D).…”

Section: Bioengineered Microenvironment For Early Embryo Culture In Vmentioning

confidence: 99%

“…58 Under 3D in vitro culture conditions, ESCs with self-assembling properties can develop into natural embryos-like structures. 18,34,42,62,63 For example, Harrison et al 41 found that in 3D matrigel, after 96 hours, ESCs can self-assemble into a cylindrical structure similar to a natural mouse embryo ( Figure 3D). The discovery provides a powerful platform for studying the physical and molecular mechanisms of embryonic development.…”

Section: Static Culture Platformsmentioning

confidence: 99%

Bioengineered microenvironment to culture early embryos

Guo

Wang

et al. 2020

Cell Proliferation

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The abnormalities of early post‐implantation embryos can lead to early pregnancy loss and many other syndromes. However, it is hard to study embryos after implantation due to the limited accessibility. The success of embryo culture in vitro can avoid the challenges of embryonic development in vivo and provide a powerful research platform for research in developmental biology. The biophysical and chemical cues of the microenvironments impart significant spatiotemporal effects on embryonic development. Here, we summarize the main strategies which enable researchers to grow embryos outside of the body while overcoming the implantation barrier, highlight the roles of engineered microenvironments in regulating early embryonic development, and finally discuss the future challenges and new insights of early embryo culture.

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“…Finally, our observations suggest that the regulation of progesterone signaling by PR-A and PR-B might have diverged in the human lineage, meaning that animal models of progesterone signaling may not adequately recapitulate human biology. Thus, the development of organoid models of the human maternal-fetal interface (Rinehart et al 1988;Boretto et al 2017;Turco et al 2017;Turco et al 2018;Marinić and Lynch 2019) will be important to understand human-specific aspects of progesterone signaling.…”

Section: Conclusion Caveats and Limitationsmentioning

confidence: 99%

Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage

Marinić

Lynch²

2019

Preprint

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AbstractThe steroid hormone progesterone, acting through the progesterone receptor (PR), a ligand-activated DNA-binding transcription factor, plays an essential role in regulating nearly every aspect of female reproductive biology. While many reproductive traits regulated by PR are conserved in mammals, Catarrhine primates evolved several derived traits including spontaneous decidualization, menstruation, and a divergent (and unknown) parturition signal, suggesting that PR may also have evolved divergent functions in Catarrhines. There is conflicting evidence, however, whether the progesterone receptor gene (PGR) was positively selected in the human lineage. Here we show thatPGRevolved rapidly in the human stem-lineage (as well as other Catarrhine primates), which likely reflects an episode of relaxed selection intensity rather than positive selection. Coincident with the episode of relaxed selection intensity, ancestral sequence resurrection and functional tests indicate that the major human PR isoforms (PR-A and PR-B) evolved divergent functions in the human stem-lineage. These results suggest that the regulation of progesterone signaling by PR-A and PR-B may also have diverged in the human lineage and that non-human animal models of progesterone signaling may not faithfully recapitulate human biology.

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Trophoblast organoids as a model for maternal–fetal interactions during human placentation

Cited by 509 publications

References 36 publications

Derivation of macaque trophoblast stem cells

Derivation of macaque trophoblast stem cells

Bioengineered microenvironment to culture early embryos

Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage

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