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Activation of neural stem cells (NSCs) correlates with improved functional outcomes in mouse models of injury. In the murine brain, NSCs have been extensively characterized and comprise (1) primitive NSCs (pNSCs) and (2) definitive NSCs (dNSCs). pNSCs are the earliest cells in the NSC lineage giving rise to dNSCs in the embryonic and adult mouse brain. pNSCs are quiescent under baseline conditions and can be activated upon injury. Herein, we asked whether human pNSCs and dNSCs can be isolated during the maturation of human cerebral organoids (COs) and activated by drugs known to regulate mouse NSC behavior. We demonstrate that self-renewing, multipotent pNSC and dNSC populations are present in human COs and express genes previously characterized in mouse NSCs. The drug NWL283, an inhibitor of apoptosis, reduced cell death in COs but did not improve NSC survival. Metformin, a drug used to treat type II diabetes that is known to promote NSC activation in mice, was found to expand human NSC pools. Together, these findings are the first to identify and characterize human pNSCs, advancing our understanding of the human NSC lineage and highlighting drugs that enhance their activity. [ABSTRACT FROM AUTHOR]

Stroke is the leading cause of adult disability worldwide. The majority of stroke survivors are left with devastating functional impairments for which few treatment options exist. Recently, a number of studies have used ectopic expression of transcription factors that direct neuronal cell fate with the intention of converting astrocytes to neurons in various models of brain injury and disease. While there have been reports that question whether astrocyte-to-neuron conversion occurs in vivo, here, we have asked if ectopic expression of the transcription factor Neurod1 is sufficient to promote improved functional outcomes when delivered in the subacute phase following endothelin-1-induced sensory–motor cortex stroke. We used an adeno-associated virus to deliver Neurod1 from the short GFAP promoter and demonstrated improved functional outcomes as early as 28 days post-stroke and persisting to at least 63 days post-stroke. Using Cre-based cell fate tracking, we showed that functional recovery correlated with the expression of neuronal markers in transduced cells by 28 days post-stroke. By 63 days post-stroke, the reporter-expressing cells comprised ~20% of all the neurons in the perilesional cortex and expressed markers of cortical neuron subtypes. Overall, our findings indicate that ectopic expression of Neurod1 in the stroke-injured brain is sufficient to enhance neural repair. [ABSTRACT FROM AUTHOR]

Stroke results in neuronal cell death, which causes long-term disabilities in adults. Treatment options are limited and rely on a narrow window of opportunity. Apoptosis inhibitors demonstrate efficacy in improving neuronal cell survival in animal models of stroke. However, many inhibitors non-specifically target apoptosis pathways and high doses are needed for treatment. We explored the use of a novel caspase-3/7 inhibitor, New World Laboratories (NWL) 283, with a lower IC50 than current caspase-3/7 inhibitors. We performed in vitro and in vivo assays to determine the efficacy of NWL283 in modulating cell death in a preclinical model of stroke. In vitro and in vivo assays show that NWL283 enhances cell survival of neural precursor cells. Delivery of NWL283 following stroke enhances endogenous NPC migration and leads to increased neurogenesis in the stroke-injured cortex. Furthermore, acute NWL283 administration is neuroprotective at the stroke injury site, decreasing neuronal cell death and reducing microglia activation. Coincident with NWL283 delivery for 8 days, stroke-injured mice exhibited improved functional outcomes that persisted following cessation of the drug. Therefore, we propose that NWL283 is a promising therapeutic warranting further investigation to enhance stroke recovery. [ABSTRACT FROM AUTHOR]

Neural precursor cells (NPCs or stem and progenitor cells) are promising in transplantation strategies to treat an injury to the central nervous system, such as a spinal cord injury (SCI), because of their ability to differentiate into neurons and glia. Transplantation studies to date have met with limited success for a number of reasons, including poor cell survival. One way to encourage cell survival in injured tissue is to provide the cells with a scaffold to enhance their survival, their integration, and potentially their differentiation into appropriate cell types. Towards this end. four amine-functionalized hydrogens were screened in vitro for adult murine NPC viability, migration, and differentiation: chitosan, poly(oligoethylene oxide dimethacrylate-co-2-amino ethyl methacrylate), blends of poly(oligoethylene oxide dimethacrylate-co-2-amino ethyl methacrylate), and poly( vinyl alcohol), and poly(glycerol dimethacrylate-co-2-amino ethyl methacrylate). The greatest cell viability was found on chitosan at all times examined, Chitosan had the greatest surface amine content and the lowest equilibrium water content, which likely contributed to the greater NPC viability observed over three weeks in culture. Only chitosan supported survival of multipotent stem cells and the differentiation of the progenitors into neurons, astrocytes, and oligodendrocytes. Plating intact NPC colonies revealed greater cell migration on chitosan relative to the other hydrogens. Importantly, long term cultures on chitosan showed no significant difference in total cell counts over time, suggesting no net cell growth. Together, these findings reveal chitosan as a promising material for the delivery of adult NPC cell-based therapies. Key words: biomaterials, chitosan, hydrogels, stem cells, cell viability. Les cellules neurales precurseurs (CNP, cellules souches et progeniteurs) sont tres prometteuses dans les strategies de transplantation pour le traitement de blessures an systeme nerveux central, tel un traumatisme an cordon medullaire (TCM), en raison de leur habilite a differencier les neurones des cellules gliales. Jusqu'a maintenant, les etudes de transplantation n'ont eu que des succes mitiges en raison de divers facteurs, dont le faible taux de survie des cellules. Une facon d'augmenter ce taux de survie dans les tissus traumatises est de fournir des cellules comportant un echafaudage permettant d'augmenter leur survie. leur integration et eventuellement leur differentiation dans les divers types de cellules. A cette fin, quatre hydrogels portant des amines fonctionnalisees, le chilosane, le poly(dimethacrylate de l'oxyde d'oligoelhylene-co-2-aminomethacrylate d'ethyle), des melanges de poly(dimethacrylate de l'oxyde d'oligoethylene-co-2-aminomeihacrylaie d'elhyle) et d'alcool polyvinylique el du poly(dimethacrylate de glycerol-co-2-aminomethaerylate d'ethyle) ont ete soumis a une evaluation in vitro, pour la migration, la differentiation et viabilite de cellules neurales precurseurs de murine adulte. Dans tous les cas, la viabilite la plus grande des cellules a ete observee avec le chitosane. Le chitosane comporte le degre le plus eleve d'amine de surface et la quantite la plus faible d'eau en equilibre, ce qui a vraisemblable- ment contribue a la plus grande viabilite des cellules neurales precurseurs sur une periode de trois semaines dans les cultures. Seul le chitosane permet de supporter la survie de cellules souches a plusieurs composantes et de differencier les progeniteurs en neurones, astrocytes et oligodendrocytes. L'examen de plaques de colonies intactes de cellules neurales precurseurs met en evidence que la migration de ces cellules sur le chitosane est beaucoup plus rapide que sur les autres hydrogels. Les cultures a long terme sur le chitosane ne presentent pas de differences signiflcatives dans les comptages totaux de cellules en fonction du temps; cette observation est importante puisqu'elle suggere qu'il ne supporte aucune croissance nette de cellules. Toutes ces observations mettent en evidence le fait que le chitosane est un materiau plein de promesses pour conduire a des therapies basees sur les cellules neurales precurseurs adultes. Mots-cles : biomateriaux, chitosane, hydrogels, cellules souches, viabilite des cellules. [Traduit par la Redaction] doi: 10.1139/V0.-171, Introduction Traumatic injury to the adult mammalian spinal cord causes irrevocable damage, producing an environment that inhibits regrowth of damaged axons. (1-4) The initial damage to the cord is compounded [...]

Embryonic cortical neural stem cells apparently have a transient existence, as they do not persist in the adult cortex. We sought to determine the fate of embryonic cortical stem cells by following [Emx1.sup.IREScre]; LacZ/ EGFP double-transgenic murine cells from midgestation into adulthood. Lineage tracing in combination with direct cell labeling and time-lapse video microscopy demonstrated that Emx1-lineage embryonic cortical stem cells migrate ventrally into the striatal germinal zone (GZ) perinatally and intermingle with striatal stem cells. Upon integration into the striatal GZ, cortical stem cells down-regulate Emx1 and up-regulate Dlx2, which is a homeo-box gene characteristic of the developing striatum and striatal neural stem cells. This demonstrates the existence of a novel dorsal-to-ventral migration of neural stem cells in the perinatal forebrain.