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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

The study of congenital virus infections in humans requires suitable ex vivo platforms for the species-specific events during embryonal development. A prominent example for these infections is rubella virus (RV) which most commonly leads to defects in ear, heart, and eye development. We applied teratogenic RV to human induced pluripotent stem cells (iPSCs) followed by differentiation into cells of the three embryonic lineages (ecto-, meso-, and endoderm) as a cell culture model for blastocyst- and gastrulation-like stages. In the presence of RV, lineage-specific differentiation markers were expressed, indicating that lineage identity was maintained. However, portrait analysis of the transcriptomic expression signatures of all samples revealed that mock- and RV-infected endodermal cells were less related to each other than their ecto- and mesodermal counterparts. Markers for definitive endoderm were increased during RV infection. Profound alterations of the epigenetic landscape including the expression level of components of the chromatin remodeling complexes and an induction of type III interferons were found, especially after endodermal differentiation of RV-infected iPSCs. Moreover, the eye field transcription factors RAX and SIX3 and components of the gene set vasculogenesis were identified as dysregulated transcripts. Although iPSC morphology was maintained, the formation of embryoid bodies as three-dimensional cell aggregates and as such cellular adhesion capacity was impaired during RV infection. The correlation of the molecular alterations induced by RV during differentiation of iPSCs with the clinical signs of congenital rubella syndrome suggests mechanisms of viral impairment of human development.

Details

Title
Teratogenic Rubella Virus Alters the Endodermal Differentiation Capacity of Human Induced Pluripotent Stem Cells
Author
Bilz, Nicole C 1 ; Willscher, Edith 2 ; Binder, Hans 2   VIAFID ORCID Logo  ; Janik Böhnke 1 ; Stanifer, Megan L 3   VIAFID ORCID Logo  ; Hübner, Denise 1 ; Boulant, Steeve 4   VIAFID ORCID Logo  ; Liebert, Uwe G 1   VIAFID ORCID Logo  ; Claus, Claudia 1   VIAFID ORCID Logo 

 Institute of Virology, University of Leipzig, 04103 Leipzig, Germany 
 Interdisciplinary Center for Bioinformatics, University of Leipzig, 04107 Leipzig, Germany 
 Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany 
 Schaller Research Group at CellNetworks, Department of Infectious Diseases, Virology, Heidelberg University Hospital, 69120 Heidelberg, Germany; Research Group “Cellular Polarity and Viral Infection” (F140), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 
First page
870
Publication year
2019
Publication date
2019
Publisher
MDPI AG
e-ISSN
20734409
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2548340845
Copyright
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.