Ottoboni, L. | bioRxiv Science

bioRxiv2021

Heparin protects human neural progenitor cells from Zika Virus-induced cell death and preserves their differentiation into mature neural-glia cells

Zika virus (ZIKV) is an arbovirus member of the Flaviviridae family that causes severe congenital brain anomalies in infected fetuses. Human neural progenitor cells (hNPCs) are highly permissive to ZIKV infection, causing inhibition of cell proliferation concomitant with an induction of cell death. We previously demonstrated that pharmaceutical-grade heparin inhibited virus-induced cell death with minor effects on in vitro virus replication in ZIKV-infected hNPCs. Here we show that heparin prevented ZIKV-induced intracellular vacuoles, a signature characteristic of paraptosis, but also inhibited necrosis and apoptosis of hNPCs when grown as neurospheres (NS). Furthermore, heparin preserved the differentiation of both ZIKV-infected human-induced pluripotent stem cells (hiPSC) derived-NPCs and fetus-derived NPCs into neural-glial cells. Collectively, these results highlight the potential neuroprotective effect of heparin that could be re-purposed and exploited to drive the development of novel agents for preventing ZIKV damage.

microbiology↗

bioRxiv2020

Multiple sclerosis iPSC-derived oligodendroglia conserve their intrinsic properties to functionally interact with axons and glia in vivo

The remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic regulators of the oligodendroglial biology or reflect MS oligodendrocyte intrinsic properties. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient, dysmyelinating mouse model, to compare side-by-side induced pluripotent stem-cell-derived O4+ oligodendroglia from MS and healthy donors following their engraftment in the developing CNS. We show that the MS-progeny survives, proliferates and differentiates into oligodendrocytes to the same extent as controls. Quantitative multi-parametric imaging indicates that MS and control oligodendrocytes generate equal amounts of myelin, with bona-fide nodes of Ranvier and promote equal restoration of their host slow conduction. Moreover, the MS-derived progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glial cells. Thus, MS pluripotent stem cell-derived progeny fully integrates into functional axo-glial and glial-glial components, reinforcing the view that the MS oligodendrocyte differentiation block is not due to intrinsic oligodendroglial deficits. These biological findings as well as the fully integrated human-murine chimeric model should facilitate the development of pharmacological or cell-based therapies to promote CNS remyelination. One Sentence SummaryMultiple Sclerosis oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia and glia-glia connections after engraftment in the murine CNS, reinforcing the view that the MS oligodendrocyte differentiation block is not due to major intrinsic oligodendroglial deficits but most likely to environmental conditions.

neuroscience↗