Sirtuin1 is required for proper trophoblast differentiation and placental development in mice

Kanaga Arul Nambi Rajan, Marwa Khater, Francesca Soncin, Donald Pizzo, Matteo Moretto-Zita, Jonathan Pham, Orysya Stus, Pooja Iyer, Veronique Tache, Louise C. Laurent, Mana M. Parast

Research output: Contribution to journalArticle

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Abstract

Introduction Placental insufficiency, arising from abnormal trophoblast differentiation and function, is a major cause of fetal growth restriction. Sirtuin-1 (Sirt1) is a ubiquitously-expressed NAD-dependent protein deacetylase which plays a key role in numerous cellular processes, including cellular differentiation and metabolism. Though Sirt1 has been widely studied, its role in placentation and trophoblast differentiation is unclear. Method Sirt1-heterozygous mice were mated and evaluated at various points during embryogenesis. In situ hybridization and immunohistochemistry were used to further characterize the placental phenotype of Sirt1-null mice. Wild-type (WT) and Sirt1-null mouse trophoblast stem cell (TSC) lines were derived from e3.5 littermate blastocysts. These cells were then evaluated at various points following differentiation. Differentiation was evaluated by expression of lineage specific markers using qPCR and flow cytometry, as well as Matrigel invasion assays. Global gene expression changes were evaluated using microarray-based RNA profiling; changes in specific pathways were validated using qPCR and western blot. Results In the absence of Sirt1, both embryos and placentas were small, with placentas showing abnormalities in both the labyrinthine layer and junctional zone. Sirt1-null TSCs exhibited an altered phenotype in both undifferentiated and differentiated states, phenotypes which corresponded to changes in pathways relevant to both TSC maintenance and differentiation. Specifically, Sirt1-null TSC showed blunted differentiation, and appeared to be suspended in an Epcamhigh trophoblast progenitor state. Discussion Our results suggest that Sirt1 is required for proper TSC differentiation and placental development.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalPlacenta
Volume62
DOIs
StatePublished - Feb 1 2018

Fingerprint

Sirtuin 1
Placentation
Trophoblasts
Stem Cells
Phenotype
Placenta
Cell Differentiation
Placental Insufficiency
Blastocyst
Fetal Development
NAD
Embryonic Development
In Situ Hybridization
Flow Cytometry
Embryonic Structures
Western Blotting
Immunohistochemistry
Maintenance
RNA

Keywords

  • Differentiation
  • Fetal development
  • Fetal growth restriction
  • Placenta
  • Stem cells
  • Trophoblast

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology
  • Developmental Biology

Cite this

Arul Nambi Rajan, K., Khater, M., Soncin, F., Pizzo, D., Moretto-Zita, M., Pham, J., ... Parast, M. M. (2018). Sirtuin1 is required for proper trophoblast differentiation and placental development in mice. Placenta, 62, 1-8. https://doi.org/10.1016/j.placenta.2017.12.002

Sirtuin1 is required for proper trophoblast differentiation and placental development in mice. / Arul Nambi Rajan, Kanaga; Khater, Marwa; Soncin, Francesca; Pizzo, Donald; Moretto-Zita, Matteo; Pham, Jonathan; Stus, Orysya; Iyer, Pooja; Tache, Veronique; Laurent, Louise C.; Parast, Mana M.

In: Placenta, Vol. 62, 01.02.2018, p. 1-8.

Research output: Contribution to journalArticle

Arul Nambi Rajan, K, Khater, M, Soncin, F, Pizzo, D, Moretto-Zita, M, Pham, J, Stus, O, Iyer, P, Tache, V, Laurent, LC & Parast, MM 2018, 'Sirtuin1 is required for proper trophoblast differentiation and placental development in mice', Placenta, vol. 62, pp. 1-8. https://doi.org/10.1016/j.placenta.2017.12.002
Arul Nambi Rajan K, Khater M, Soncin F, Pizzo D, Moretto-Zita M, Pham J et al. Sirtuin1 is required for proper trophoblast differentiation and placental development in mice. Placenta. 2018 Feb 1;62:1-8. https://doi.org/10.1016/j.placenta.2017.12.002
Arul Nambi Rajan, Kanaga ; Khater, Marwa ; Soncin, Francesca ; Pizzo, Donald ; Moretto-Zita, Matteo ; Pham, Jonathan ; Stus, Orysya ; Iyer, Pooja ; Tache, Veronique ; Laurent, Louise C. ; Parast, Mana M. / Sirtuin1 is required for proper trophoblast differentiation and placental development in mice. In: Placenta. 2018 ; Vol. 62. pp. 1-8.
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AU - Moretto-Zita, Matteo

AU - Pham, Jonathan

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AU - Iyer, Pooja

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AU - Laurent, Louise C.

AU - Parast, Mana M.

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N2 - Introduction Placental insufficiency, arising from abnormal trophoblast differentiation and function, is a major cause of fetal growth restriction. Sirtuin-1 (Sirt1) is a ubiquitously-expressed NAD-dependent protein deacetylase which plays a key role in numerous cellular processes, including cellular differentiation and metabolism. Though Sirt1 has been widely studied, its role in placentation and trophoblast differentiation is unclear. Method Sirt1-heterozygous mice were mated and evaluated at various points during embryogenesis. In situ hybridization and immunohistochemistry were used to further characterize the placental phenotype of Sirt1-null mice. Wild-type (WT) and Sirt1-null mouse trophoblast stem cell (TSC) lines were derived from e3.5 littermate blastocysts. These cells were then evaluated at various points following differentiation. Differentiation was evaluated by expression of lineage specific markers using qPCR and flow cytometry, as well as Matrigel invasion assays. Global gene expression changes were evaluated using microarray-based RNA profiling; changes in specific pathways were validated using qPCR and western blot. Results In the absence of Sirt1, both embryos and placentas were small, with placentas showing abnormalities in both the labyrinthine layer and junctional zone. Sirt1-null TSCs exhibited an altered phenotype in both undifferentiated and differentiated states, phenotypes which corresponded to changes in pathways relevant to both TSC maintenance and differentiation. Specifically, Sirt1-null TSC showed blunted differentiation, and appeared to be suspended in an Epcamhigh trophoblast progenitor state. Discussion Our results suggest that Sirt1 is required for proper TSC differentiation and placental development.

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