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Sakr, M.

Publications and source records attributed to Sakr, M..

2 recordsLinked to original sources

A Novel GelMA-OrnMA Electrically Conductive Bioink for Developing Engineered Neural Tissues

Electrical conductivity is a crucial requirement of matrices for developing engineered neural tissues. A conductive matrix not only supports cell growth but also provides potential to stimulate the cells. However, electrically conductive matrices often require inclusion of synthetic polymers, nanomaterials and large number of ionic species. While enhancing electrical conductivity, often properties like transparency, mechanical stiffness and biocompatibility are compromised which can render the resulting matrices partially suitable for neural tissue engineering. Further, the byproducts of matrix degradation can have unforeseen influences. Therefore, electrically active matrices are required which provide a suitable combination of electrical conductivity, mechanical properties and biocompatibility. In this work, a novel biomaterial is described which results in optically transparent, electrically conductive and highly biocompatible matrices along with ability to match the native neural tissue stiffness. Using gelatin methacryloyl (GelMA) as base hydrogel, we covalently incorporated zwitterionic functional groups to obtain a composite matrix. The zwitterion moieties were derived from Ornithine by synthesizing ornithine methacryloyl (OrnMA) and blending with GelMA inks. Through systematic characterization we demonstrated the suitability of GelMA-OrnMA hydrogels in providing mechanical stiffness matching the native neural tissues, supporting proliferation of human astrocytes in 3D culture and electrical conductivity in the range required for electrically active cell types like astrocytes. Owing to their electrical conductivity, these matrices also influenced the growth of astrocytes which manifested as significant changes in their organization and morphology. These findings suggest that GelMA-OrnMA has immense potential as a bioink for developing engineered neural tissues.

bioengineering↗

TREM2 is downregulated by HSV1 in microglia and involved in antiviral defense in the brain

Immunological control of viral infection in the brain is essential for immediate protection, but also for long-term maintenance of brain integrity. As the primary resident immune cell of the brain, microglia protect against viral infections through key macrophage functions, including release of the antiviral type I interferons (IFN-I) and clearance of infected cells. Microglia express the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), which can bind viral DNA leading to signaling through stimulator of interferon genes (STING), and downstream immune activation. Here we report that herpes simplex virus (HSV) 1 infection of microglia leads to activation of IFN-I genes and pro-inflammatory cytokines. However, HSV1 also down-regulated expression of a subset of genes, including genes in the pathway engaged by the microglial receptor triggering receptor expressed on myeloid cells-2 (TREM2). Knockdown experiments revealed that TREM2 is important for viral activation of cGAS-STING signaling in microglia, induction of IFN-I, and phagocytosis of HSV1 infected neurons. Consequently, TREM2 depletion increased susceptibility to HSV1 infection in human microglia-neuron co-cultures and mice in vivo. Mechanistically, we show that TREM2 is essential for phosphorylation of STING, and downstream activation of the IFN-inducing transcription factor IRF3. We conclude that TREM2 is a novel component of the antiviral immune response in microglia, crucial for immediate host defense against HSV1 in the brain. Since both TREM2 loss-of-function mutations and HSV1 serological status are linked to development of Alzheime[r]s disease (AD), this work opens the question whether defects in TREM2 could predispose to impaired viral clearance and post-infection pathological neurological changes.

immunology↗