Advances in Zika Virus Research: Stem Cell Models, Challenges, and Opportunities

Abstract

SummaryThe re-emergence of Zika virus (ZIKV) and its suspected link with various disorders in newborn and adults led the World Health Organization to declare a global health emergency. In response, the stem cell field quickly established platforms for modeling ZIKV exposure using human pluripotent stem cell-derived neural progenitors and brain organoids, fetal tissues and animal models. These efforts provided significant insight into cellular targets, pathogenesis and underlying biological mechanisms of ZIKV infection as well as platforms for drug testing. Here we review the remarkable progress in stem cell-based ZIKV research and discuss current challenges and future opportunities.

Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins

“…Zika virus (ZIKV) belongs to the flavivirus genus in the Flaviviridae family, which includes many significant pathogens, such as dengue virus (DENV), yellow fever virus, West Nile virus, and Japanese encephalitis virus (Lindenbach et al, 2007; Ming et al, 2016). In the wake of the recent ZIKV outbreak, the greatest concern has been the link between ZIKV infection during pregnancy and congenital neurodevelopmental birth defects, such as microcephaly (Rasmussen et al, 2016).…”

“…In the wake of the recent ZIKV outbreak, the greatest concern has been the link between ZIKV infection during pregnancy and congenital neurodevelopmental birth defects, such as microcephaly (Rasmussen et al, 2016). Since the World Health Organization declared a Public Health Emergency of International Concern (Heymann et al, 2016), tremendous progress has been made in both clinical and basic ZIKV research (Li et al, 2016b; Ming et al, 2016). ZIKV was found in microcephalic brains of fetuses from women infected with ZIKV during pregnancy (Driggers et al, 2016; Mlakar et al, 2016) and ZIKV has been shown to directly infect cortical neural progenitors in various experimental model systems, including human induced pluripotent stem cell (iPSC)-derived and fetal brain tissue-derived neural progenitors in monolayer, 3D neurosphere and brain organoid cultures, and in mice (Li et al, 2016b; Ming et al, 2016).…”

“…ZIKV was found in microcephalic brains of fetuses from women infected with ZIKV during pregnancy (Driggers et al, 2016; Mlakar et al, 2016) and ZIKV has been shown to directly infect cortical neural progenitors in various experimental model systems, including human induced pluripotent stem cell (iPSC)-derived and fetal brain tissue-derived neural progenitors in monolayer, 3D neurosphere and brain organoid cultures, and in mice (Li et al, 2016b; Ming et al, 2016). At the cellular level, productive infection of neural progenitors by ZIKV delays cell cycle progression and increases cell death (Ming et al, 2016). At the molecular level, ZIKV infection leads to dysregulation of many signaling pathways (Wen et al, 2017).…”

Human induced pluripotent stem cells for modelling neurodevelopmental disorders

“…This was further evidenced by abnormal progression of cell cycle, increased cell death/apoptosis, and disrupted neurogenesis by the same study as well as many others 167–173 . For a more in-depth overview of the subject see review by Ming et al 174 .…”

A previously undetected pathology of Zika virus infection

“…Since then, considerable progress has been made in understanding the neurological consequences of ZIKV infection 1 . In 2016, we and others 1–3 showed that ZIKV is neurotropic and can directly and productively infect human neural progenitor cells (NPCs) in both 2D and 3D cell culture models of cortical development, resulting in reduced proliferation and increased death of neural progenitors. In parallel, early models of ZIKV infection in pregnant mice showed direct infection of fetal NPCs, viral replication in the embryonic brain, and microcephalic-like outcomes in offspring at birth 4 .…”