Search

Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early Dual SMAD and WNT inhibition course is necessary and sufficient to establish robust and lasting cortical organoid NSC identity, efficiently suppressing non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC-specification capacity. Accordingly, this method selectively enriches for outer radial glia NSCs, which cyto-architecturally demarcate well-defined outer sub-ventricular-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD and WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring of fundamental molecular and cyto-architectural features of cortical development and meaningful disease modelling.

Alzheimer&rsquo, s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-&alpha, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-&beta, plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD.

Stem cell-based therapies for neurodegenerative diseases aim at halting clinical deterioration by regeneration and by providing local support for damaged tissue. Mesenchymal stem cells (MSCs) hold great potential for cell therapy as they can be efficiently derived from adult tissue, ex vivo expanded in culture and safely transplanted autologously. MSCs were also shown to be able to differentiate toward neural fates and to secrete a broad range of factors able to promote nervous tissue maintenance and repair. Moreover, upon transplantation, MSCs were shown capable of homing toward lesioned areas, implying their potential use as vehicles for therapeutic agents administration. Indeed, various advantageous effects were reported following human MSCs transplantation into rodent models of neurodegenerative diseases, such as neurotrophic factor-mediated protection, enhanced neurogenesis, modulation of inflammation, and abnormal protein aggregate clearance. Per journal style, most nonstandard abbreviations must be used at least two times in the abstract to be retained; NTF was used once and thus has been deleted. Recent studies have also used ex vivo manipulation for enhanced expression of potentially favorable factors, by so exploiting the homing capacity of MSCs for effective expression at the lesion site. Here, we will summarize current advancements in MSCs-based therapies for neurodegenerative diseases. We will examine the roles of central mechanisms suggested to mediate the beneficial effects of MSCs-based therapy and consider the augmentation of these mechanisms for superior clinical outcomes in rodent models of neurodegeneration as well as in clinical trials. Stem Cells 2017;35:1867-1880.

Background & Aim Myeloperoxidase (MPO) is a potent enzyme expressed mostly by neutrophils, that catalyzes the formation of reactive oxygen species (ROS), mainly hypochlorous acid. MPO is a primary mediator of neutrophils oxidative stress response and was shown to be essential for the formation of neutrophils extracellular traps (NETs). Upon secretion, MPO was also shown to attach to blood endothelial cells and promote their degradation, making it a therapeutic target in multiple clinical incidences, including neurodegenerative disorders. Here, we aimed to assess the role of neutrophil-derived MPO in 5XFAD model of AD. Methods, Results & Conclusion For that purpose, we subjected 5XFAD mice to myeloablative irradiation and bone marrow-repopulation from MPO Knock-out (KO) mice to form 'MPO KO-5XFAD' mice. MPO KO-5XFAD mice exhibited improvement in their risk assessment behavior, as measured by the 'Elevated plus maze/ test and the 'Open field' test, when compared to 5XFAD mice transplanted with WT cells (termed 'WT-5XFAD'). Remarkably, MPO KO-5XFAD mice also showed improved spatial recognition and learning, as was evident in the 'Y-maze' test, the 'Morris water maze' test and by 'Contextual fear conditioning' test. Hippocampal RNA expression analysis by QPCR indicated decreased expression of proinflammatory cytokines in MPO KO-5XFAD mice, along with decreased blood brain barrier damage and reduced expression of murine APOE. Together, these results indicate a substantial involvement of blood-derived oxidative damage in mouse model of AD, and assign MPO as a potential therapeutic target in AD.

Decoding heterogeneity of pluripotent stem cell (PSC)-derived neural progeny is fundamental for revealing the origin of diverse progenitors, for defining their lineages, and for identifying fate determinants driving transition through distinct potencies. Here we have prospectively isolated consecutively appearing PSC-derived primary progenitors based on their Notch activation state. We first isolate early neuroepithelial cells and show their broad Notch-dependent developmental and proliferative potential. Neuroepithelial cells further yield successive Notch-dependent functional primary progenitors, from early and midneurogenic radial glia and their derived basal progenitors, to gliogenic radial glia and adult-like neural progenitors, together recapitulating hallmarks of neural stem cell (NSC) ontogeny. Gene expression profiling reveals dynamic stage-specific transcriptional patterns that may link development of distinct progenitor identities through Notch activation. Our observations provide a platform for characterization and manipulation of distinct progenitor cell types amenable for developing streamlined neural lineage specification paradigms for modelling development in health and disease., Profiling pluripotent stem cell (PSC)-derived neural progeny is of fundamental interest for characterizing stem cell differentiation. Here, the authors analyse neural progenitors consecutively derived from human PSCs, showing dynamic stage-specific transcriptional patterns for distinct neural progenitors.