Zika virus alters osteogenic lineage progression of human mesenchymal stromal cells

Noreen Mumtaz, Amel Dudakovic, Asha Nair, Marijke Koedam, Johannes P T M van Leeuwen, Marion P G Koopmans, Barry Rockx*, Andre J van Wijnen, Bram C J van der Eerden*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Downloads (Pure)


Arboviruses target bone forming osteoblasts and perturb bone remodeling via paracrine factors. We previously reported that Zika virus (ZIKV) infection of early-stage human mesenchymal stromal cells (MSCs) inhibited the osteogenic lineage commitment of MSCs. To understand the physiological interplay between bone development and ZIKV pathogenesis, we employed a primary in vitro model to examine the biological responses of MSCs to ZIKV infection at different stages of osteogenesis. Precommitted MSCs were infected at the late stage of osteogenic stimulation (Day 7) with ZIKV (multiplicity of infection of 5). We observe that MSCs infected at the late stage of differentiation are highly susceptible to ZIKV infection similar to previous observations with early stage infected MSCs (Day 0). However, in contrast to ZIKV infection at the early stage of differentiation, infection at a later stage significantly elevates the key osteogenic markers and calcium content. Comparative RNA sequencing (RNA-seq) of early and late stage infected MSCs reveals that ZIKV infection alters the mRNA transcriptome during osteogenic induction of MSCs (1251 genes). ZIKV infection provokes a robust antiviral response at both stages of osteogenic differentiation as reflected by the upregulation of interferon responsive genes (n > 140). ZIKV infection enhances the expression of immune-related genes in early stage MSCs while increasing cell cycle genes in late stage MSCs. Remarkably, ZIKA infection in early stage MSCs also activates lipid metabolism-related pathways. In conclusion, ZIKV infection has differentiation stage-dependent effects on MSCs and this mechanistic understanding may permit the development of new therapeutic or preventative measures for bone-related effects of ZIKV infection.

Original languageEnglish
Pages (from-to)379-392
Number of pages14
JournalJournal of Cellular Physiology
Issue number2
Early online date20 Dec 2022
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information:
This work was supported in part by ZonMW under grant number 522003001 (project: ZikaRisk “Risk of Zika virus introductions for the Netherlands”) and by the European Union's Horizon 2020 Research and Innovation Program under grant number 734548 (project: ZIKAlliance). Additional support was provided by NIH (R01 AR049069 to A. J. v. W.) and the generosity of William and Karen Eby. Gijs. P. van Nierop and Muriel Aguilar‐Bretones are acknowledged for their contribution in the preparation of rebuttal.

Publisher Copyright:
© 2022 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.


Dive into the research topics of 'Zika virus alters osteogenic lineage progression of human mesenchymal stromal cells'. Together they form a unique fingerprint.

Cite this