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Neuroepithelial cell

Neuroepithelial cells are the primary neural progenitor cells that constitute the pseudostratified epithelium lining the neural tube during early vertebrate embryonic development, originating from the neuroectoderm and serving as multipotent stem cells capable of self-renewal and differentiation into all neurons and glial cells of the central nervous system.^[1] These cells form through primary neurulation, where the neural plate folds and fuses to create the neural tube, establishing the foundational structure of the brain and spinal cord.^[2] Characterized by their apical-basal polarity, neuroepithelial cells maintain tight adherens junctions at the apical surface facing the ventricular lumen and extend processes to the basal lamina, enabling coordinated behaviors such as interkinetic nuclear migration, where nuclei move along the apicobasal axis during the cell cycle to facilitate proliferation at the ventricular surface.^[1] Early in development, they primarily undergo symmetric proliferative divisions to expand the progenitor pool, ensuring sufficient cells for subsequent neurogenesis.^[3] As development progresses, their division modes shift to asymmetric neurogenic divisions, producing one progenitor and one postmitotic neuron, or symmetric neurogenic divisions yielding two neurons, thereby initiating the generation of diverse neuronal subtypes in a spatiotemporal manner.^[1] Neuroepithelial cells transition into radial glial cells around the onset of neurogenesis, retaining many of their progenitor properties while acquiring elongated radial processes that guide neuronal migration and provide scaffolds for cortical layering.^[4] This transformation is marked by changes in gene expression, such as upregulation of glial markers like GFAP, and is crucial for the continued production of neurons and later glia across brain regions.^[1] Disruptions in neuroepithelial cell polarity, division, or migration can lead to neural tube defects, highlighting their essential role in normal CNS formation.^[2]

Definition and Characteristics

Morphology and Distribution

Neuroepithelial cells form a pseudostratified columnar epithelium that constitutes the wall of the developing neural tube. These cells exhibit pronounced apical-basal polarity, with short apical processes extending to contact the ventricular surface and long basal processes reaching the pial surface, thereby spanning the full thickness of the tube wall.^[5]^[6] At their apical ends, the cells are interconnected by adherens junctions, which maintain the structural integrity and cohesion of the epithelial sheet.^[7] These cells exhibit an elongated morphology.^[8] During the cell cycle, neuroepithelial cells undergo interkinetic nuclear migration, a process in which nuclei migrate apically toward the ventricular surface during the G2 phase and mitosis, and basally during the S and G1 phases of interphase. This dynamic movement contributes to the pseudostratified appearance of the epithelium, as nuclei are positioned at varying depths across the cell layer.^[9]^[10] Neuroepithelial cells are initially distributed uniformly, lining the entire lumen of the neural tube from its earliest formation. In mice, this lining is established around embryonic day 8.5 (E8.5), corresponding to approximately the third week of human gestation, when the neural plate begins to fold and the tube closes.^[11]^[2] This uniform arrangement persists along the rostrocaudal axis of the neural tube during primary neurulation.

Molecular Markers and Identification

Neuroepithelial cells, as neural stem cells during early embryonic development, are characterized by the expression of specific molecular markers that underscore their progenitor identity and multipotency. Nestin, an intermediate filament protein, serves as a prominent cytoskeletal marker for these cells, reflecting their undifferentiated state and capacity for self-renewal. Similarly, the transcription factor Sox2 is essential for maintaining pluripotency and neural fate specification, while Pax6, a paired box transcription factor, regulates neurogenesis and is highly expressed in neuroepithelial progenitors to control their proliferation and differentiation potential.^[12] At the apical surface, where neuroepithelial cells form junctional complexes, markers such as Prominin-1 (also known as CD133), a pentaspan membrane glycoprotein, localize to plasma membrane protrusions and indicate stem cell properties within the ventricular zone. N-cadherin, a calcium-dependent cell adhesion molecule, is integral to adherens junctions in the subapical region, supporting cell-cell interactions that preserve epithelial integrity and progenitor maintenance. In contrast, basal markers like Laminin, a key component of the extracellular matrix in the basal lamina, facilitate attachment and polarity, anchoring neuroepithelial cells to the underlying substrate during neural tube formation.^[13]^[14]^[15] The Notch signaling pathway, particularly through upregulation of the Notch1 receptor, plays a critical role in sustaining the neuroepithelial progenitor state by inhibiting premature differentiation and promoting symmetric cell divisions. In their undifferentiated phase, these cells lack neuronal markers such as β-III tubulin, which emerges only upon commitment to a neuronal lineage, thereby distinguishing progenitors from post-mitotic neurons.^[16] Identification of neuroepithelial cells relies on techniques like immunohistochemistry, which detects these markers through antibody staining to visualize expression patterns in tissue sections, and single-cell RNA sequencing, which profiles transcriptomic signatures to differentiate neuroepithelial cells from adjacent ectodermal populations based on gene expression clusters.^[12]^[17]

Embryonic Development

Neural Tube Formation

Neuroepithelial cells originate during the early stages of embryonic development through a process known as neural induction, where the neuroectoderm is specified from the ectodermal layer. This induction is primarily driven by signals from the underlying notochord, which secretes Sonic hedgehog (Shh), a key morphogen that promotes ventral neural fate and inhibits non-neural ectodermal differentiation.^[18] Concurrently, the surface ectoderm contributes by inhibiting bone morphogenetic protein (BMP) signaling through secreted antagonists such as Noggin and Chordin, which are expressed in the notochord and dorsal mesoderm; this BMP inhibition is essential for the ectoderm to adopt a neural identity rather than an epidermal one.^[19]^[20] These signaling pathways act in concert during gastrulation, transforming the presumptive neuroectoderm into the neural plate, from which neuroepithelial cells emerge as the initial population of neural progenitors.^[21] The formation of the neural tube, or primary neurulation, follows neural induction and involves dynamic morphological changes orchestrated by neuroepithelial cells. The neural plate initially thickens due to the apical constriction of neuroepithelial cells, leading to the elevation of the lateral edges as neural folds.^[22] These folds then converge toward the midline, where their tips fuse to enclose the central lumen, forming the neural tube that will develop into the central nervous system.^[23] This process relies on coordinated behaviors of neuroepithelial cells, including shape changes and cytoskeletal rearrangements, to achieve tube closure without gaps. In human gestation, primary neurulation occurs between days 18 and 28 post-fertilization, with the anterior neuropore closing around day 25 and the posterior neuropore by day 28.^[23] In mice, this timeline corresponds to embryonic days 8 to 10 (E8-E10).^[24] Failure of neural tube closure disrupts the integrity of the developing central nervous system and can result in severe congenital defects. For instance, incomplete fusion at the cranial end leads to anencephaly, characterized by the absence of major brain structures, while caudal failures cause spina bifida, where the spinal cord remains exposed.^[25] These open neural tube defects arise from disruptions in the neurulation process and highlight the critical timing of closure, as the neural tube must seal completely by embryonic day 28 in humans to prevent such malformations.^[26] Post-closure, neuroepithelial cells initiate proliferation to expand the neural tube, a process detailed in subsequent developmental stages.

Proliferation Mechanisms

Neuroepithelial cells in the early neural tube primarily undergo symmetric cell divisions, which expand the progenitor pool by producing two identical daughter cells that remain within the neuroepithelium. This mode of division predominates during initial phases of central nervous system (CNS) development, enabling rapid population growth to establish the foundational layers of the neural tube.^[6] As development progresses, neuroepithelial cells transition to asymmetric divisions, where one daughter cell retains progenitor identity for self-renewal while the other commits toward differentiation, balancing pool maintenance with the onset of neurogenesis.^[27] Proliferation is tightly regulated by signaling pathways, including Wnt/β-catenin, which promotes cell cycle progression and progenitor expansion in the developing forebrain.^[28] Similarly, fibroblast growth factor (FGF) signaling drives mitotic activity and sustains survival in anterior neuroepithelial regions through β-catenin-dependent mechanisms.^[29] The cell cycle in these early-stage neuroepithelial cells typically lasts 8-12 hours, allowing for frequent divisions that support exponential growth.^[30] A key feature of neuroepithelial proliferation is interkinetic nuclear migration (INM), where nuclei oscillate along the apical-basal axis in synchrony with the cell cycle: they move basally during S-phase for DNA synthesis and return apically for mitosis.^[31] This process ensures ordered division at the ventricular surface while maintaining epithelial integrity. High expression of cyclins, such as Cyclin D1, facilitates the G1/S transition by activating cyclin-dependent kinases, thereby accelerating progression through the cell cycle and enhancing proliferative capacity.^[32] In mice, the proliferation rate of neuroepithelial progenitors peaks around embryonic day 12 (E12), coinciding with intense forebrain expansion and the generation of millions of progenitors to fuel subsequent neuronal production.^[33] During mitosis, cells exhibit apical constriction to facilitate cytokinesis, as noted in morphological studies. This high proliferative phase underscores the dynamic balance required for CNS scaling.

Differentiation and Transition

Neuroepithelial cells undergo a critical transition during early neurogenesis, shifting from symmetric proliferative divisions to asymmetric divisions that generate one progenitor cell and one post-mitotic neuron. This process is regulated by the activation of proneural basic helix-loop-helix (bHLH) transcription factors, such as Neurogenin1 (Neurog1) and Neurogenin2 (Neurog2), which promote neuronal fate commitment in the differentiating daughter cell while maintaining progenitor identity in the other.^[34] These asymmetric divisions typically begin around embryonic day 11 (E11) in mice, marking the onset of neurogenic phases where cell divisions balance self-renewal and differentiation.^[35] Concomitant with these fate decisions, neuroepithelial cells morphologically and molecularly transition into radial glial cells between approximately E11 and E13 in mice, characterized by the elongation of radial processes spanning the ventricular zone to the pial surface and the upregulation of glial markers such as vimentin.^[36]^[37] This shift transforms the pseudostratified neuroepithelium into a scaffold of bipolar radial glia, which not only serve as progenitors but also provide migratory guidance for newborn neurons toward the cortical plate.^[38] The transition reflects a broader change from multipotent neuroepithelial progenitors to glial-like radial glial cells capable of generating diverse neuronal and glial lineages.^[39] A key event in this differentiation pathway is the delamination of intermediate progenitors from the ventricular zone, where these cells retract their apical processes and migrate basally to undergo further divisions away from the ventricular surface.^[40] This delamination, often following asymmetric divisions of radial glia, amplifies neuronal output by allowing intermediate progenitors to produce additional neurons in the subventricular zone. Proliferative divisions in preceding stages enable the accumulation of neuroepithelial cells necessary for this transition.^[41]

Adult Neural Stem Cells

Persistence and Locations

In the adult mammalian brain, a subset of neural stem cells persists with neuroepithelial-like characteristics, primarily in the ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ) of the hippocampus. These cells, often identified as quiescent type B1 cells in the V-SVZ, derive from embryonic radial glia and retain features such as apico-basal polarity and primary cilia that contact the ventricular lumen, echoing the organization of embryonic neuroepithelium.^[42] Lineage tracing studies using Nestin-Cre systems have confirmed their persistence, demonstrating that these progenitors originate from slowly dividing embryonic populations around E13.5–E15.5 and contribute to the adult stem cell pool without significant turnover until activation.^[43] These adult neural progenitors express markers indicative of retained neuroepithelial traits, such as Sox2 and Nestin alongside astrocytic proteins.^[44] These neuroepithelial-like cells are predominantly located lining the walls of the lateral ventricles in the V-SVZ, where type B cells form a niche interfacing with the cerebrospinal fluid, and in the SGZ of the dentate gyrus, where radial glia-like cells (RGLs) reside adjacent to the granule cell layer. Despite their astrocytic morphology—characterized by GFAP expression, intermediate filaments, and processes extending to blood vessels—they harbor stem-like potential, generating transit-amplifying progenitors upon activation.^[45] In the V-SVZ, type B cells occupy positions that allow direct ventricular contact via cilia, facilitating environmental sensing, while SGZ RGLs integrate into the hippocampal circuitry.^[42] Unlike their embryonic counterparts, which proliferate rapidly with cell cycles lasting hours (typically 8–24 hours), adult neuroepithelial-like cells exhibit markedly slower division rates, often entering quiescence for weeks to months to preserve the stem cell pool. This prolonged quiescence, with asymmetric divisions occurring every 1–3 months in type B cells, contrasts sharply with the symmetric proliferative expansions of embryonic neuroepithelium. Their persistence and activity are further modulated by aging, which reduces progenitor numbers through impaired lysosomal function and diminished cerebrospinal fluid signaling, as well as environmental factors like vascular niche interactions.^[46]

Role in Neurogenesis

Adult neuroepithelial-like stem cells in the subventricular zone (SVZ) serve as the primary source of new neurons in the adult brain, generating interneurons for the olfactory bulb through a well-defined lineage progression. These stem cells, classified as type B cells, exhibit characteristics reminiscent of embryonic neuroepithelial cells, including the ability to undergo asymmetric division to maintain the stem cell pool while producing transit-amplifying progenitors. Type B cells give rise to type C cells, which rapidly proliferate and differentiate into migrating neuroblasts known as type A cells. These neuroblasts form chains and travel tangentially via the rostral migratory stream (RMS) to the olfactory bulb, where they integrate as GABAergic interneurons, supporting olfactory discrimination and circuit plasticity.^[47]^[48] However, the occurrence of substantial adult neurogenesis in the human SVZ is controversial, with some evidence suggesting it is minimal or absent after early adulthood.^[49] The process of SVZ neurogenesis is tightly regulated by the local niche environment, which includes ependymal cells lining the lateral ventricle and vascular structures. Ependymal cells provide structural support and secrete factors such as Shh and BMP antagonists to modulate type B cell quiescence and activation, preventing premature exhaustion of the stem cell reservoir. Vascular endothelial cells contribute trophic signals like VEGF and EGF, promoting proliferation and survival while anchoring stem cells to the niche; this vascular association is crucial for asymmetric divisions that mirror embryonic mechanisms but are adapted for adult homeostasis. In adult humans, the rate of new neuron addition from the SVZ is lower than in rodents and remains debated due to species-specific differences in niche organization.^[47]^[48] In the hippocampal subgranular zone (SGZ), neuroepithelial-like type 1 stem cells drive granule cell neurogenesis, essential for hippocampal-dependent learning and memory formation. These stem cells proliferate to yield intermediate progenitors that mature into dentate gyrus granule cells, enhancing synaptic plasticity and pattern separation. The process is potently upregulated by brain-derived neurotrophic factor (BDNF), which promotes progenitor survival and dendritic arborization, and by exercise-induced factors such as IGF-1 and VEGF, which boost proliferation through enhanced vascularization and reduced apoptosis. In adult humans, approximately 700 new granule cells are incorporated into the dentate gyrus of each hippocampus daily in young adults, although the extent of this neurogenesis is subject to ongoing debate, with some studies questioning its persistence beyond adolescence.^[50] However, hippocampal neurogenesis declines with age, exhibiting roughly a 50% reduction by age 50 due to diminished progenitor proliferation and increased cell death.^[51]^[52]

Repair and Regeneration

Following injury such as stroke or trauma, neuroepithelial-derived neural stem cells in the adult subventricular zone (SVZ) exhibit upregulated proliferation, generating neuroblasts that migrate toward damaged regions like the peri-infarct striatum to support repair. In rodent models of focal stroke, this response markedly increases SVZ neurogenesis, with chains of migrating neuroblasts extending to the striatum, where they differentiate into medium spiny neurons—the primary neuronal type lost in such injuries—contributing to partial neuronal replacement.^[53] This process amplifies baseline SVZ neurogenesis, which under physiological conditions maintains limited neuronal turnover.^[54] Despite this potential, regeneration remains incomplete in mammals, as the majority of SVZ-derived cells post-injury adopt non-neuronal fates, such as undifferentiated precursors or astrocytes, with fewer than 2% maturing into neurons even after weeks.^[54] Reactive gliosis often predominates, forming a glial scar that limits neuronal integration; for instance, traumatic brain injury shifts neural stem cell fate toward neurogenesis at the expense of astrogliogenesis, yet newborn neurons display abnormal morphology, including reduced dendritic spines, hindering functional incorporation.^[55] Studies in rodent stroke models indicate that SVZ activation supports modest recovery, with newborn neurons aiding synaptic and vascular plasticity, though overall neuronal replacement accounts for only a small fraction of lost cells.^[54] Human postmortem evidence from cases of ischemic stroke corroborates this response, revealing elevated numbers of proliferating SVZ cells and neuroblasts, particularly in aged individuals, suggesting a conserved repair mechanism despite advanced age.^[56] Enrichment of growth factors like epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) further enhances this potential; VEGF, acting via VEGFR2 receptors, boosts SVZ proliferation by up to 2.5-fold and promotes neuroblast differentiation after traumatic brain injury, while EGF synergistically supports precursor expansion.^[57]^[58] These factors not only increase newborn neuron numbers but also correlate with reduced lesion volumes and improved motor outcomes in preclinical models.^[58]

Pathological Conditions

Neoplastic Disorders

Neoplastic disorders involving neuroepithelial cells primarily manifest as gliomas and glioneuronal tumors, arising from dysregulated proliferation of these progenitors or their derivatives. These tumors range from low-grade, indolent lesions to aggressive malignancies, often driven by genetic alterations that disrupt normal differentiation pathways. Key examples include dysembryoplastic neuroepithelial tumor (DNT) and oligodendroglial tumors, with high-grade forms like glioblastoma multiforme (GBM) linked to neuroepithelial origins through dedifferentiation mechanisms.^[59] Dysembryoplastic neuroepithelial tumor (DNT) is a benign glioneuronal neoplasm classified as WHO grade 1, typically arising in the temporal lobe of children and young adults. It is histologically characterized by a mucin-rich nodules containing oligodendrocyte-like cells and floating neurons in a specific glioneuronal element. DNT accounts for approximately 1.2% of neuroepithelial tumors in patients under 20 years old and is strongly associated with intractable epilepsy, often presenting as the primary symptom leading to surgical intervention.^[60]^[61]^[62] Oligodendroglial tumors represent grade II-III diffuse gliomas that originate from neuroepithelial progenitors, defined molecularly by isocitrate dehydrogenase (IDH) mutations and complete 1p/19q codeletion as a hallmark genetic feature. These mutations, particularly IDH1 R132H, occur early in gliomagenesis and promote oncogenic transformation by altering cellular metabolism and epigenetic regulation. The 1p/19q codeletion confers sensitivity to chemotherapy and is prognostic for improved survival compared to non-codeleted gliomas.^[63]^[64]^[65] Glioblastoma multiforme (GBM), a high-grade glioma, can trace its origins to neuroepithelial cells via dedifferentiation of mature astrocytes or glial progenitors into stem-like states. EGFR gene amplification is a frequent alteration in these high-grade tumors, occurring in up to 57% of primary GBM cases and driving aggressive growth through enhanced receptor signaling. In contrast, BRAF V600E mutations are identified in some low-grade neuroepithelial tumors, such as certain glioneuronal lesions, and are associated with MAPK pathway activation, offering potential therapeutic targets with BRAF inhibitors.^[66]^[67]^[68]

Developmental Malformations

Developmental malformations of neuroepithelial cells arise primarily from disruptions during embryogenesis, leading to structural anomalies in the central nervous system without neoplastic transformation. These include fluid-filled cysts and defects in neural tube closure, resulting from impaired proliferation, migration, or differentiation of neuroepithelial progenitors. Such abnormalities often stem from genetic or environmental factors affecting key signaling pathways, manifesting as congenital conditions that may remain asymptomatic or cause neurological deficits depending on severity and location.^[69] Neuroepithelial cysts, also known as glioependymal cysts, represent benign, congenital lesions originating from incomplete separation or displacement of neuroepithelial tissue during neural tube formation. These fluid-filled structures are typically lined by cuboidal or columnar ependymal-like epithelium resting on a glial layer, distinguishing them from other cystic lesions. They are rare and often incidental findings, though larger cysts can exert mass effect leading to symptoms like headache or hydrocephalus. Classification differentiates arachnoid cysts, which are extra-axial with meningeal (mesothelial) lining and located in subarachnoid spaces, from intraventricular neuroepithelial cysts, which are intra-axial with ependymal or glial components and arise within ventricular systems.^[70]^[71] Holoprosencephaly and neural tube defects exemplify malformations due to failed neuroepithelial cell proliferation or migration. Holoprosencephaly results from disruptions in the Sonic hedgehog (Shh) signaling pathway, causing incomplete forebrain division and midline defects, as seen in Shh-null models where ventral neuroepithelial patterning fails. Neural tube defects, such as spina bifida, affect about 1 in 1,000 births globally and arise from inadequate closure of the caudal neural tube, often linked to folate deficiency that impairs DNA methylation and neuroepithelial cell division. In folate-deficient models, reduced proliferation hinders the morphogenetic movements required for tube closure, underscoring the role of nutritional factors in neuroepithelial function.^[69]^[72]

Research Advances

In Vitro Modeling

In vitro modeling of neuroepithelial cells has advanced significantly through three-dimensional (3D) culture systems derived from induced pluripotent stem cells (iPSCs), enabling the recapitulation of early brain development stages. Brain organoids, first established in 2013, self-organize from iPSCs into structures containing neuroepithelial layers that mimic radial organization and cortical layering observed in vivo. These models differentiate iPSCs into neuroectodermal progenitors, forming ventricular-like zones with apical-basal polarity characteristic of neuroepithelial cells. Assembloids extend this approach by fusing distinct organoids, such as forebrain and midbrain spheroids, to study inter-regional interactions and circuit formation. A key technique for generating neuroepithelial cells in these models involves directed differentiation protocols using dual SMAD inhibition, which blocks BMP and TGF-β signaling to promote neural induction and the formation of neuroepithelial rosettes—cylindrical structures resembling the neural tube. This method, originally described in 2009, yields high-efficiency conversion of human iPSCs into PAX6-positive neuroepithelial progenitors within 10-14 days, facilitating scalable production for organoid assembly. However, organoids exhibit variability in size, typically ranging from 1-5 mm in diameter, and cellular heterogeneity due to diffusion-limited nutrient supply, which can be mitigated by incorporating vascular networks through co-culture with endothelial cells or genetic engineering for angiogenesis. Single-cell transcriptomic analyses have provided detailed maps of neuroepithelial heterogeneity in these models. A 2021 atlas of early human brain organoids highlighted diverse neuroepithelial subpopulations, including radial glia-like cells, mirroring embryonic stages from 5-9 post-conception weeks and revealing transcriptional gradients along the ventricular surface. More recent assembloid studies in 2025 have modeled forebrain-midbrain interactions, demonstrating dopaminergic neuron integration and synaptic connectivity relevant to Parkinson's disease pathogenesis. These in vitro systems have been instrumental in studying infectious impacts on neuroepithelial proliferation. Since 2016, brain organoids infected with Zika virus have shown reduced progenitor proliferation, increased apoptosis, and disrupted cortical layering, attributing microcephaly phenotypes to direct targeting of neuroepithelial cells by the virus. Ongoing refinements, such as vascularized assembloids, continue to enhance model fidelity for developmental and disease research.

Therapeutic Potential

Neuroepithelial-derived neural progenitor cells hold promise for stem cell transplantation therapies aimed at repairing spinal cord injuries (SCI). In rodent models of thoracic SCI, transplantation of human neuroepithelial stem cells has demonstrated the ability to form relay circuits that bridge injured areas, leading to significant functional recovery; for instance, grafted cells improved Basso Mouse Scale (BMS) scores from less than 1 (no movement) to 4 (occasional stepping) in mice with severe injuries, and up to 5 (consistent stepping) in milder cases, compared to controls that remained below 3.^[73] Similar engraftment of induced pluripotent stem cell (iPSC)-derived neuroepithelial progenitors in mouse contusion models has supported histological regeneration and motor function gains, with cells surviving, differentiating into neurons and glia, and integrating into host circuitry without tumor formation.^[74] Research also explores neuroepithelial cell modulation in psychiatric disorders, particularly depression, where enhancing neurogenesis in regions like the subventricular zone (SVZ) and hippocampus could underlie therapeutic effects. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) have been shown to increase neural progenitor cell proliferation in these areas; in human postmortem studies of major depressive disorder (MDD) patients treated with SSRIs, hippocampal dentate gyrus progenitor numbers rose dramatically to approximately 19,800 per section from 1,100 in untreated cases, representing over a 17-fold increase.^[75] Animal models corroborate this, with chronic SSRI administration boosting SVZ and hippocampal proliferation by promoting survival and differentiation of neuroepithelial-like progenitors, potentially contributing to antidepressant efficacy.^[76] In oncology, neuroepithelial markers expressed on glioblastoma (GBM) cells—such as Nestin and Sox2—serve as targets for emerging therapies. Phase I clinical trials as of 2025 investigate oncolytic viruses delivered via neural stem cells to exploit these markers for selective tumor lysis; for example, the NSC-CRAd-S-pk7 agent, using a modified HB1.F3 neural stem cell line loaded with tumor-selective adenovirus, is being tested in recurrent high-grade gliomas, with the first patient enrolled in 2023 and ongoing multi-center enrollment evaluating safety across up to four intracerebral doses.^[77] Neural chimeras, formed by transplanting neuroepithelial progenitors into host brains, further aid therapeutic development by modeling integration; in rodent studies, these chimeras reveal progenitor plasticity, with donor cells migrating and forming functional connections in the host parenchyma, informing strategies for brain repair.^[78] Despite these advances, challenges persist in translating neuroepithelial cell therapies. Immune rejection remains a hurdle, even with autologous iPSC-derived cells, due to potential immunogenicity from reprogramming or incomplete histocompatibility, necessitating immunosuppression or gene editing for better matching.^[79] Ethical concerns also arise, particularly around iPSC sourcing from human embryos or gametes, raising issues of consent, equity in access, and the risk of tumorigenicity from residual undifferentiated cells, which could form teratomas post-transplantation.^[80] In vitro models provide a critical testing ground for optimizing these approaches before clinical use.^[81]

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