The Antioxidant Phytochemical Schisandrin A Promotes Neural Cell Proliferation and Differentiation after Ischemic Brain Injury

Schisandrin A (SCH) is a natural bioactive phytonutrient that belongs to the lignan derivatives found in Schisandra chinensis fruit. This study aims to investigate the impact of SCH on promoting neural progenitor cell (NPC) regeneration for avoiding stroke ischemic injury. The promoting effect of SCH on NPCs was evaluated by photothrombotic model, immunofluorescence, cell line culture of NPCs, and Western blot assay. The results showed that neuron-specific class III beta-tubulin (Tuj1) was positive with Map2 positive nerve fibers in the ischemic area after using SCH. In addition, Nestin and SOX2 positive NPCs were significantly (p < 0.05) increased in the penumbra and core. Further analysis identified that SCH can regulate the expression level of cell division control protein 42 (Cdc42). In conclusion, our findings suggest that SCH enhanced NPCs proliferation and differentiation possible by Cdc42 to regulated cytoskeletal rearrangement and polarization of cells, which provides new hope for the late recovery of stroke.

Zika Virus Overview: Transmission, Origin, Pathogenesis, Animal Model and Diagnosis

Zika virus (ZIKV) was first discovered in 1947 in Uganda. ZIKV did not receive substantial attention until Brazil hosted the 2016 Summer Olympic Games, and ZIKV reached a global audience. ZIKV is a flavivirus transmitted chiefly through mosquito bites, sexual intercourse and, to a lesser extent, breastfeeding. The recent discovery of how ZIKV causes congenital neurodevelopmental defects, including microcephaly, has led to reevaluation of the importance of the interaction of ZIKV with centrosome organization, because centrosomes play an important role in cell division. When ZIKV disrupts centrosome organization and mitotic abnormalities, neural progenitor differentiation is altered, thereby resulting in cell cycle arrest, increased apoptosis and inhibition of neural progenitor cell differentiation; subsequently, abnormalities in neural cell development can result in microcephaly. To aid in the understanding of the importance of ZIKV infection, this review article provides an overview of its history, transmission routes, pathogenesis, animal models and diagnosis.

Optimizing fibrin hydrogel toward effective neural progenitor cell delivery in spinal cord injury

Transplantation of neural progenitor cell (NPC) possessing the potential to differentiate into neurons may guard against spinal cord injury (SCI)- associated neuronal trauma. We propose that autologous-like NPC may reduce post-transplant immune response. The study used the rat SCI model to prove this concept. For isolation and expansion of rat NPC for cell-based SCI therapy, the in vitro protocol standardized with human NPC seemed suitable. The primary aim of this study is to select a cell/neural tissue-compatible biomaterial for improving NPC survival in vivo. The composition of the fibrin hydrogel is adjusted to obtain degradable, porous, and robust fibrin strands for supporting neural cell attachment, migration, and tissue regeneration. This study employed NPC culture to evaluate the cytocompatibility and suitability of the hydrogel, composed by adding graded concentrations of thrombin to a fixed fibrinogen concentration. The microstructure evaluation by scanning electron microscope guided the selection of a suitable composition for delivering the embedded cells. On adding more thrombin, fibrinogen clotted quickly but reduced porosity, pore size, and fiber strand thickness. The high activity of thrombin also affected NPC morphology and the in vitro cell survival. The selected hydrogel carried viable NPC and retained them at the injury site post-transplantation. The fibrin hydrogel played a protective role throughout the transfer process by providing cell attachment sites and survival signals. The fibrin and NPC together regulated the immune response at the SCI site reducing ED1+ve/ED2+ve macrophages in the early period of 8 to 16 days after injury. Migration of β-III tubulin+ve neural-like cells into the fibrin-injected control SCI is evident. The continuous use of a non-neurotoxic fibrin matrix could be a convenient strategy for in vitro NPC preparation, minimally invasive cell delivery, and better transplantation outcome.

BRCA1 and ELK-1 regulate Neural Progenitor Cell Fate in the Optic Tectum in response to Visual Experience in Xenopus laevis tadpoles

In developing Xenopus tadpoles, the optic tectum begins to receive patterned visual input while visuomotor circuits are still undergoing neurogenesis and circuit assembly. This visual input regulates neural progenitor cell fate decisions such that maintaining tadpoles in the dark increases proliferation, expanding the progenitor pool, while visual stimulation promotes neuronal differentiation. To identify regulators of activity-dependent neural progenitor cell fate, we used RNA-Seq to profile the transcriptomes of proliferating neural progenitor cells and newly-differentiated immature neurons. Out of 1,130 differentially expressed (DE) transcripts, we identified six DE transcription factors which are predicted to regulate the majority of the other DE transcripts. Here we focused on Breast cancer 1 (BRCA1) and the ETS-family transcription factor, ELK-1. BRCA1 is known for its role in cancers, but relatively little is known about its potential role in regulating neural progenitor cell fate. ELK-1 is a multifunctional transcription factor which regulates immediate early gene expression. We investigated the effect of BRCA1 and ELK-1 on activity-regulated neurogenesis in the tadpole visual system using in vivo timelapse imaging to monitor the fate of turbo-GFP-expressing SOX2+ neural progenitor cells in the optic tectum. Our longitudinal in vivo imaging analysis shows that knockdown of either BRCA1 or ELK-1 altered the fates of neural progenitor cells, and furthermore that the effects of visual experience on neurogenesis depend on BRCA1 expression, while the effects of visual experience on neuronal differentiation depend on ELK-1 expression. These studies provide insight into the potential mechanisms by which neural activity affects neural progenitor cell fate.

Oral and injected tamoxifen alter adult hippocampal neurogenesis in female and male mice

Inducible Cre recombinase facilitates temporal control of genetic recombination in numerous transgenic model systems, a feature which has made it a popular tool for studies of adult neurogenesis. One of the most common forms of inducible Cre, CreERT2, requires activation by the synthetic estrogen tamoxifen (TAM) to initiate recombination of LoxP-flanked sequences. To date, most studies deliver TAM via intraperitoneal injection. But the introduction of TAM-infused commercial chows has recently expanded the possible modes of TAM delivery. Despite the widespread use of TAM-inducible genetic models in adult neurogenesis research, the comparative efficiency and off-target effects of TAM administration protocols is surprisingly infrequently studied. Here we compare a standard, 5 day TAM injection regimen with voluntary consumption of TAM-infused chow. First, we used adult NestinCreERT2;Rosa-LoxP-STOP-LoxP-EYFP reporter mice to show that 2 weeks of TAM chow and 5 days of injections led to LoxP recombination in a similar phenotypic population of neural stem and progenitor cells in the adult dentate gyrus. However, TAM chow resulted in substantially less overall recombination than injections. TAM administration also altered adult neurogenesis, but in different ways depending on administration route: TAM injection disrupted neural progenitor cell proliferation 3 weeks after TAM, whereas TAM chow increased neuronal differentiation of cells generated during the diet period. These findings provide guidance for selection of TAM administration route and appropriate controls in adult neurogenesis studies using TAM-inducible Cre mice. They also highlight the need for better understanding of off-target effects of TAM in other neurological processes and organ systems.

D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain

d-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the d-stereoisomer of the amino acid with the fastest spontaneous racemization ratein vitro in vitro, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and a stereospecific luciferase assay, we identify endogenous d-cysteine in the mammalian brain. We identify serine racemase (SR), which generates the N-methyl-d-aspartate (NMDA) glutamate receptor coagonist d-serine, as a candidate biosynthetic enzyme for d-cysteine. d-cysteine is enriched more than 20-fold in the embryonic mouse brain compared with the adult brain. d-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by ∼50%, effects not shared with d-serine or l-cysteine. The antiproliferative effect of d-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence of d-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen for d-cysteine–binding proteins in NPCs by immunoprecipitation with a d-cysteine–specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putative d-cysteine–binding protein. Together, these results establish endogenous mammalian d-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.