The eyeball's connected to the brain ball.

How does the human eye develop in concert with the brain to create a functioning visual system? In this issue of Cell Stem Cell, Gabriel et al. (2021) report the development of eye-like structures from forebrain organoids with light sensitivity, signal processing, and connectivity, which moves us toward answering this complex question.

Assessing patient perception of risk in ocular stem cell therapies.

A wide variety of stem cell-derived therapies are under development for the treatment of retinal degeneration. In order to better understand patient perspectives about these therapies, we assessed risk tolerance using an in-person survey of 178 patients at an academic eye center. Risk of malignancy served as a hypothetical, readily understood, and serious adverse event to be considered in trade for potential visual improvement from a stem cell-derived treatment.

Differentiating Human Pluripotent Stem Cells to Vascular Endothelial Cells for Regenerative Medicine, Tissue Engineering, and Disease Modeling.

Vasculature plays a vital role in human biology as blood vessels transport nutrients and oxygen throughout the body. Endothelial cells (ECs), specifically, are key as they maintain barrier functions between the circulating blood and the surrounding tissues. ECs derived from human pluripotent stem cells (hPSCs) are utilized to study vascular development and disease mechanisms within in vitro models.

High-content image-based analysis and proteomic profiling identifies Tau phosphorylation inhibitors in a human iPSC-derived glutamatergic neuronal model of tauopathy.

Mutations in MAPT (microtubule-associated protein tau) cause frontotemporal dementia (FTD). MAPT mutations are associated with abnormal tau phosphorylation levels and accumulation of misfolded tau protein that can propagate between neurons ultimately leading to cell death (tauopathy). Recently, a p.

STAU2 binds a complex RNA cargo that changes temporally with production of diverse intermediate progenitor cells during mouse corticogenesis.

STAU2 is a double-stranded RNA-binding protein enriched in the nervous system. During asymmetric divisions in the developing mouse cortex, STAU2 preferentially distributes into the intermediate progenitor cell (IPC), delivering RNA molecules that can impact IPC behavior. Corticogenesis occurs on a precise time schedule, raising the hypothesis that the cargo STAU2 delivers into IPCs changes over time.

ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules.

Treatment with hypoxia-mimetics protects cultured rat Schwann cells against oxidative stress-induced cell death.

Schwann cell (SC) grafts promote axon regeneration in the injured spinal cord, but transplant efficacy is diminished by a high death rate in the first 2-3 days postimplantation. Both hypoxic preconditioning and pharmacological induction of the cellular hypoxic response can drive cellular adaptations and improve transplant survival in a number of disease/injury models. Hypoxia-inducible factor 1 alpha (HIF-1α), a regulator of the cellular response to hypoxia, is implicated in preconditioning-associated protection.

3D Image Analysis of the Complete Ventricular-Subventricular Zone Stem Cell Niche Reveals Significant Vasculature Changes and Progenitor Deficits in Males Versus Females with Aging.

With age, neural stem cell (NSC) function in the adult ventricular-subventricular zone (V-SVZ) declines, reducing memory and cognitive function in males; however, the impact on females is not well understood. To obtain a global view of how age and sex impact the mouse V-SVZ, we constructed 3D montages after multiplex immunostaining, and used computer-based 3D image analysis to quantify data across the entire niche at 2, 18, and 22 months. We discovered dramatic sex differences in the aging of the V-SVZ niche vasculature, which regulates NSC activity: females showed increased diameter but decreased vessel density with age, while males showed decreased diameter and increased tortuosity and vessel density.

Enhanced CNS transduction from AAV.PHP.eB infusion into the cisterna magna of older adult rats compared to AAV9.

The development of high efficiency, central nervous system (CNS) targeting AAV-based gene therapies is necessary to address challenges in both pre-clinical and clinical investigations. The engineered capsids, AAV.PHP.

Methylene blue is a potent and broad-spectrum inhibitor against Zika virus and .

Many flaviviruses including the Dengue virus (DENV), Zika virus (ZIKV), West Nile virus, Yellow Fever virus, and Japanese encephalitis virus are significant human pathogens, unfortunately without any specific therapy. Here, we demonstrate that methylene blue, an FDA-approved drug, is a broad-spectrum and potent antiviral against Zika virus and Dengue virus both and . We found that methylene blue can considerably inhibit the interactions between viral protease NS3 and its NS2B co-factor, inhibit viral protease activity, inhibit viral growth, protect 3D mini-brain organoids from ZIKV infection, and reduce viremia in a mouse model.

The optic nerve lamina region is a neural progenitor cell niche.

Retinal ganglion cell axons forming the optic nerve (ON) emerge unmyelinated from the eye and become myelinated after passage through the optic nerve lamina region (ONLR), a transitional area containing a vascular plexus. The ONLR has a number of unusual characteristics: it inhibits intraocular myelination, enables postnatal ON myelination of growing axons, modulates the fluid pressure differences between eye and brain, and is the primary lesion site in the age-related disease open angle glaucoma (OAG). We demonstrate that the human and rodent ONLR possesses a mitotically active, age-depletable neural progenitor cell (NPC) niche, with unique characteristics and culture requirements.

Zeb2 Is a Regulator of Astrogliosis and Functional Recovery after CNS Injury.

The astrocytic response to injury is characterized on the cellular level, but our understanding of the molecular mechanisms controlling the cellular processes is incomplete. The astrocytic response to injury is similar to wound-healing responses in non-neural tissues that involve epithelial-to-mesenchymal transitions (EMTs) and upregulation in ZEB transcription factors. Here we show that injury-induced astrogliosis increases EMT-related genes expression, including Zeb2, and long non-coding RNAs, including Zeb2os, which facilitates ZEB2 protein translation.

Cell Type-Specific In Vitro Gene Expression Profiling of Stem Cell-Derived Neural Models.

Genetic and genomic studies of brain disease increasingly demonstrate disease-associated interactions between the cell types of the brain. Increasingly complex and more physiologically relevant human-induced pluripotent stem cell (hiPSC)-based models better explore the molecular mechanisms underlying disease but also challenge our ability to resolve cell type-specific perturbations. Here, we report an extension of the RiboTag system, first developed to achieve cell type-restricted expression of epitope-tagged ribosomal protein (RPL22) in mouse tissue, to a variety of in vitro applications, including immortalized cell lines, primary mouse astrocytes, and hiPSC-derived neurons.

Acute mechanical stress in primary porcine RPE cells induces angiogenic factor expression and in vitro angiogenesis.

Background: Choroidal neovascularization (CNV) is a major cause of blindness in patients with age-related macular degeneration. CNV is characterized by new blood vessel growth and subretinal fluid accumulation, which results in mechanical pressure on retinal pigment epithelial (RPE) cells. The overexpression of RPE-derived angiogenic factors plays an important role in inducing CNV.

Epigenomic and Transcriptomic Changes During Human RPE EMT in a Stem Cell Model of Epiretinal Membrane Pathogenesis and Prevention by Nicotinamide.

Epithelial to mesenchymal transition (EMT) is a biological process involved in tissue morphogenesis and disease that causes dramatic changes in cell morphology, migration, proliferation, and gene expression. The retinal pigment epithelium (RPE), which supports the neural retina, can undergo EMT, producing fibrous epiretinal membranes (ERMs) associated with vision-impairing clinical conditions, such as macular pucker and proliferative vitreoretinopathy (PVR). We found that co-treatment with TGF-β and TNF-α (TNT) accelerates EMT in adult human RPE stem cell-derived RPE cell cultures.

Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation.

Aberrant neuronal development and the persistence of mitotic cellular populations have been implicated in a multitude of neurological disorders, including Huntington's disease (HD). However, the mechanism underlying this potential pathology remains unclear. We used a modified protocol to differentiate induced pluripotent stem cells (iPSCs) from HD patients and unaffected controls into neuronal cultures enriched for medium spiny neurons, the cell type most affected in HD.

Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline.

Increasing evidence has challenged the traditional view about the immune privilege of the brain, but the precise roles of immune cells in regulating brain physiology and function remain poorly understood. Here, we report that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus of aged brains. ILC2 in the aged brain are long-lived, are relatively resistant to cellular senescence and exhaustion, and are capable of switching between cell cycle dormancy and proliferation.

Optimizing intracellular antibodies (intrabodies/nanobodies) to treat neurodegenerative disorders.

Intrabodies (both single-chain Fv and single-domain VH, VHH, and VL nanobodies) offer unique solutions to some of the challenges of delivery and target engagement posed by immunotherapeutics for the brain and other areas of the nervous system. The specificity, which includes the recognition of post-translational modifications, and capacity for engineering that characterize these antibody fragments can be especially well-focused when the genes encoding only the binding sites of the antibody are expressed intracellularly. Multifunctional constructs use fusions with peptides that can re-target antigen-antibody complexes to enhance both pharmacodynamic activity and intracellular solubility simultaneously.

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD).

Highly Differentiated Human Fetal RPE Cultures Are Resistant to the Accumulation and Toxicity of Lipofuscin-Like Material.

Purpose: The accumulation of undigestible autofluorescent material (UAM), termed lipofuscin in vivo, is a hallmark of aged RPE. Lipofuscin derives, in part, from the incomplete degradation of phagocytized photoreceptor outer segments (OS). Whether this accumulated waste is toxic is unclear.

Identifying Windows of Susceptibility by Temporal Gene Analysis.

Increased understanding of developmental disorders of the brain has shown that genetic mutations, environmental toxins and biological insults typically act during developmental windows of susceptibility. Identifying these vulnerable periods is a necessary and vital step for safeguarding women and their fetuses against disease causing agents during pregnancy and for developing timely interventions and treatments for neurodevelopmental disorders. We analyzed developmental time-course gene expression data derived from human pluripotent stem cells, with disease association, pathway, and protein interaction databases to identify windows of disease susceptibility during development and the time periods for productive interventions.

Heterogeneous Expression of SDF1 Retains Actively Proliferating Neural Progenitors in the Capillary Compartment of the Niche.

The vascular compartment of the adult brain ventricular-subventricular zone (V-SVZ) is a critical regulator of neural stem cell and progenitor function. Blood enters the V-SVZ via arteries and arterioles to capillaries that then connect with venules and veins to return blood to the heart. We found that stromal cell-derived factor 1 (SDF1) is expressed by a subpopulation of V-SVZ vessels, the capillaries, and that actively proliferating neural stem cells (NSCs) and progenitors are preferentially associated with these SDF1-positive vessels.