Cargando…

Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation

Trophoblast differentiation during early placental development is critical for successful pregnancy and aberrant differentiation causes preeclampsia and early pregnancy loss. During the first trimester, cytotrophoblasts are exposed to low oxygen tension (equivalent to~2%-3% O(2)) and differentiation...

Descripción completa

Detalles Bibliográficos
Autores principales: Kumar, Priyadarsini, Thirkill, Twanda L., Ji, Jennifer, Monte, Louise H., Douglas, Gordon C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533975/
https://www.ncbi.nlm.nih.gov/pubmed/26266541
http://dx.doi.org/10.1371/journal.pone.0135089
_version_ 1782385392600743936
author Kumar, Priyadarsini
Thirkill, Twanda L.
Ji, Jennifer
Monte, Louise H.
Douglas, Gordon C.
author_facet Kumar, Priyadarsini
Thirkill, Twanda L.
Ji, Jennifer
Monte, Louise H.
Douglas, Gordon C.
author_sort Kumar, Priyadarsini
collection PubMed
description Trophoblast differentiation during early placental development is critical for successful pregnancy and aberrant differentiation causes preeclampsia and early pregnancy loss. During the first trimester, cytotrophoblasts are exposed to low oxygen tension (equivalent to~2%-3% O(2)) and differentiation proceeds along an extravillous pathway (giving rise to invasive extravillous cytotrophoblasts) and a villous pathway (giving rise to multinucleated syncytiotrophoblast). Interstitial extravillous cytotrophoblasts invade the decidua, while endovascular extravillous cytotrophoblasts are involved in re-modelling uterine spiral arteries. We tested the idea that sodium butyrate (an epigenetic modulator) induces trophoblast differentiation in early gestation rhesus monkey trophoblasts through activation of the Wnt/β-catenin pathway. The results show that syncytiotrophoblast formation was increased by butyrate, accompanied by nuclear accumulation of β-catenin, and increased expression of EnvV2 and galectin-1 (two factors thought to be involved in trophoblast fusion). Surprisingly, the expression of GCM1 and syncytin-2 was not affected by sodium butyrate. When trophoblasts were incubated with lithium chloride, a GSK3 inhibitor that mimics Wnt activation, nuclear accumulation of β-catenin also occurred but differentiation into syncytiotrophoblast was not observed. Instead the cells differentiated to mononucleated spindle-shaped cells and showed molecular and behavioral characteristics of endovascular trophoblasts. Another highly specific inhibitor of GSK3, CHIR99021, failed to induce endovascular trophoblast characteristics. These observations suggest that activation of the Wnt/β-catenin pathway correlates with both trophoblast differentiation pathways, but that additional factors determine specific cell fate decisions. Other experiments suggested that the differential effects of sodium butyrate and lithium chloride might be explained by their effects on TNFα production. The results provide valuable tools to manipulate trophoblast differentiation in vitro and to better understand the differentiation pathways that occur during early gestation.
format Online
Article
Text
id pubmed-4533975
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-45339752015-08-24 Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation Kumar, Priyadarsini Thirkill, Twanda L. Ji, Jennifer Monte, Louise H. Douglas, Gordon C. PLoS One Research Article Trophoblast differentiation during early placental development is critical for successful pregnancy and aberrant differentiation causes preeclampsia and early pregnancy loss. During the first trimester, cytotrophoblasts are exposed to low oxygen tension (equivalent to~2%-3% O(2)) and differentiation proceeds along an extravillous pathway (giving rise to invasive extravillous cytotrophoblasts) and a villous pathway (giving rise to multinucleated syncytiotrophoblast). Interstitial extravillous cytotrophoblasts invade the decidua, while endovascular extravillous cytotrophoblasts are involved in re-modelling uterine spiral arteries. We tested the idea that sodium butyrate (an epigenetic modulator) induces trophoblast differentiation in early gestation rhesus monkey trophoblasts through activation of the Wnt/β-catenin pathway. The results show that syncytiotrophoblast formation was increased by butyrate, accompanied by nuclear accumulation of β-catenin, and increased expression of EnvV2 and galectin-1 (two factors thought to be involved in trophoblast fusion). Surprisingly, the expression of GCM1 and syncytin-2 was not affected by sodium butyrate. When trophoblasts were incubated with lithium chloride, a GSK3 inhibitor that mimics Wnt activation, nuclear accumulation of β-catenin also occurred but differentiation into syncytiotrophoblast was not observed. Instead the cells differentiated to mononucleated spindle-shaped cells and showed molecular and behavioral characteristics of endovascular trophoblasts. Another highly specific inhibitor of GSK3, CHIR99021, failed to induce endovascular trophoblast characteristics. These observations suggest that activation of the Wnt/β-catenin pathway correlates with both trophoblast differentiation pathways, but that additional factors determine specific cell fate decisions. Other experiments suggested that the differential effects of sodium butyrate and lithium chloride might be explained by their effects on TNFα production. The results provide valuable tools to manipulate trophoblast differentiation in vitro and to better understand the differentiation pathways that occur during early gestation. Public Library of Science 2015-08-12 /pmc/articles/PMC4533975/ /pubmed/26266541 http://dx.doi.org/10.1371/journal.pone.0135089 Text en © 2015 Kumar et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kumar, Priyadarsini
Thirkill, Twanda L.
Ji, Jennifer
Monte, Louise H.
Douglas, Gordon C.
Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation
title Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation
title_full Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation
title_fullStr Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation
title_full_unstemmed Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation
title_short Differential Effects of Sodium Butyrate and Lithium Chloride on Rhesus Monkey Trophoblast Differentiation
title_sort differential effects of sodium butyrate and lithium chloride on rhesus monkey trophoblast differentiation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533975/
https://www.ncbi.nlm.nih.gov/pubmed/26266541
http://dx.doi.org/10.1371/journal.pone.0135089
work_keys_str_mv AT kumarpriyadarsini differentialeffectsofsodiumbutyrateandlithiumchlorideonrhesusmonkeytrophoblastdifferentiation
AT thirkilltwandal differentialeffectsofsodiumbutyrateandlithiumchlorideonrhesusmonkeytrophoblastdifferentiation
AT jijennifer differentialeffectsofsodiumbutyrateandlithiumchlorideonrhesusmonkeytrophoblastdifferentiation
AT montelouiseh differentialeffectsofsodiumbutyrateandlithiumchlorideonrhesusmonkeytrophoblastdifferentiation
AT douglasgordonc differentialeffectsofsodiumbutyrateandlithiumchlorideonrhesusmonkeytrophoblastdifferentiation