Neural stem cells: prospects

Neural stem cells are rare cells in the central nervous system capable of self-renewal and differentiation into neurons, astrocytes, and oligodendrocytes. In adults, they reside primarily in specialized "niches," where neighboring cells and molecular signals either keep them dormant or stimulate them to divide and mature. A significant portion of neural stem cells remain "dormant," protecting the supply from depletion but allowing them to respond quickly to injury. [1]

Neural stem cells are not universal "repairers" for all situations. Their behavior is strictly dependent on their niche: the composition of their neighbors, blood supply, intercellular contacts, and local immune signals. Even within a single brain region, different areas maintain rest and activation differently, as demonstrated by modern spatial studies. This explains why some lesions are repaired better than others. [2]

Molecular signatures, such as the proteins nestin and Sox2, as well as the activity of the notch pathway and other signaling cascades, help identify neural stem cells. However, no single marker is absolute: panels of signatures and functional tests in culture and models allow us to distinguish true stem cell potential from short-lived progenitors. [3]

Today, neural stem cells are considered the foundation for regenerative technologies, from replacing lost neurons to supporting remyelination and providing "cues" to surrounding tissue. Furthermore, approaches based on induced pluripotent cells are being developed, allowing the creation of patient-related neural progenitors in the laboratory. [4]

Table 1. Main properties of neural stem cells

Property	What does this mean in practice?
Self-maintenance	The ability to store supplies for a long time without depletion
Multidirectional differentiation	Formation of neurons, astrocytes and oligodendrocytes
Niche dependence	The microenvironment makes decisions about rest and activation
Sensitivity to inflammation	Inflammatory signals may inhibit neurogenesis
[5]

Where are niches located in adults and does neurogenesis occur?

In mammals, two "canonical" niches of adult neurogenesis have been described: the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. Here, neural stem cells either maintain local interneuron circuits or supply new cells for hippocampal plasticity. These zones are distinguished by their distinctive architecture and complement of supporting cells. [6]

The extent of neurogenesis in adults remains controversial. Some studies document a decline with age and very low levels in the elderly, while others demonstrate the preservation of newly born neurons using sensitive methods and rigorous post-mortem processing. A consensus is emerging that neurogenesis in humans is preserved, but its severity is highly dependent on age, tissue condition, and methodology. [7]

Even with modest levels of neurogenesis, adult neural stem cells are important as niche "managers": they secrete factors, regulate blood vessels and glia, and help replace oligodendrocytes. This partially explains why niche-enhancing interventions can yield functional benefits without massive neuronal production. [8]

Finally, the spectrum of neurogenesis varies greatly across species. Therefore, careful extrapolation of data from models to humans is essential, and key findings should be confirmed using multiple methods, including single-cell transcriptomics and proliferation markers. [9]

Table 2. Neural stem cell niches in adults

Niche	Where is it located?	Who does it supply?	Peculiarities
Subventricular zone	Wall of the lateral ventricles	Interneurons and progenitors	Close association with ependyma and vascular elements
Subgranular zone	Dentate gyrus of the hippocampus	Granular neurons	Plasticity of memory and mood
[10]

Origin: From embryo to adult brain

During embryogenesis, neural stem cells arise from the neuroepithelium and then take the form of radial glia, which build the cortex and subcortical structures. Gradually, some cells remain in niche reserves, forming adult populations. This transition is accompanied by changes in genetic programs, metabolism, and contacts with surrounding tissues. [11]

Different waves of neural development are triggered and inhibited by niche signals, including notch, Wnt, bone morphogenetic proteins, and other factors. The coordinated shift in these "voices" determines when to recruit neurons and when to focus on glia and myelin. Misalignments can lead to developmental disruptions and an increased risk of tumor clones. [12]

In humans, time windows are shifted relative to model species, making work with organoids and induced cell models valuable. They help recreate developmental stages and test which signal combinations are critical specifically for human tissue. [13]

It was from these studies that protocols for obtaining the desired neural progenitors from induced pluripotent cells—from cortical neurons to dopaminergic progenitors for therapeutic use—grew. This brings personalized regeneration closer, although safety and standardization requirements are very high. [14]

Table 3. Stages of neural stem cell ontogenesis

Stage	Key events	What happens?
Neuroepithelium	Quick divisions, axes bookmarks	Rigid neural tube
Radial glia	Migration "ladders", neurogenesis	Cortical and subcortical neurons
Formation of niches	Selection of "reserves", setting up contacts	Adult neural stem cells
[15]

Markers and signals: how to distinguish a stem cell from a precursor cell

In practice, combinations of features are used. Nestin and Sox2 indicate immaturity and the potential for differentiation. The protein dual corticosin helps recognize migrating neuroblasts. Expression of glial fibrillary acidic protein in radial glia indicates the glial nature of the developmental "architects." But interpretation is always contextual. [16]

The notch pathway maintains quiescence and prevents premature depletion of the reserve. Wnt and Schipigel signals act as switches for proliferation and maturation. Inflammatory stimuli, on the other hand, often inhibit neurogenesis or shift the balance toward reactive glia. Therefore, assessing markers in conjunction with a niche signaling map provides a more accurate picture. [17]

Single-cell methods have made it possible to visualize the "states" of neural stem cells—from deep quiescence to active division—and their trajectories toward mature cells. These data help design culture media for culturing and expanding desired populations without losing potential. [18]

No single characteristic should be the sole basis for a clinical decision. Functional tests, stability in culture, and the absence of undesirable clones are as important as the molecular "portrait." [19]

Table 4. Useful markers and what they mean

Marker	What does it suggest?	Warning
Nestin	Cytoskeletal immaturity	It is also found in reactive glia.
Sox2	Self-sustainability, potential	Not equal to automatic "barrelness"
Dualcorticosin	Migrating neuroblasts	Marker of immature neurons
Glial fibrillary acidic protein	Radial glia and astrocytes	Contextually dependent on the niche
[20]

Research methods and their limitations

Classical nucleoside analogue markers and postmortem studies provided the first evidence for human neurogenesis. Later, lines of evidence were added from single-cell transcriptomics, spatial transcriptomics, and advanced immunohistochemistry. Different methods sometimes yield different estimates, hence the controversy. [21]

Organoids based on induced pluripotent cells have become "mini-brains in a dish," enabling the modeling of development, infection, neurodegeneration, and toxicity. They do not replace an entire organ, but are useful as a benchmark for testing hypotheses and drug discovery. The ethical and legal framework for their use is also being discussed. [22]

It is critically important to compare data from different approaches, taking into account post-mortem delays, fixation standards, and tissue processing. Methodological differences often explain the discrepancies between publications on the presence or absence of neurogenesis in adults. [23]

Clinical conclusions are based on the convergence of methods: when morphology, molecular signatures, and functional tests point in the same direction, confidence increases. This principle is especially important for the development of cell therapies. [24]

Table 5. What different methods can do

Method	What does it show?	Key limitation
Division marks and immunohistochemistry	The fact of renewal and cell types	Sensitivity and postmortem artifacts
Single-cell transcriptomics	States and trajectories	Interpretation and comparability between works
Induced cell-based organ models	Human processes in a cup	Incomplete architecture and lack of systemic influences
Visualization with contrast and labeled cells	Graft survival and integration	Resolution and specificity
[25]

Therapies: What's on the horizon and what's still in development

Dopaminergic neural precursors generated from embryonic stem cells have undergone early testing in patients with Parkinson's disease. Phase 1 studies demonstrated safety and tolerability, as well as evidence of graft survival and function, as measured by fluorodopa-enhanced positron emission tomography. This represents an important step toward replacing lost neurons in carefully selected patients. [26]

Earlier and parallel programs are testing neural stem cells in spinal cord injury. Long-term follow-up in a small group demonstrated acceptable safety and technical feasibility of implantation, although functional benefits remain variable and depend on the level and duration of injury, rehabilitation, and implant parameters. Larger, controlled studies are needed. [27]

Induced pluripotent cells are paving the way for personalized neural progenitors. The challenges of the coming years include standardizing production lines, reducing immunogenicity when using donor material, and confirming sustainable safety in the clinic. Reviews with roadmaps for clinical implementation are already appearing. [28]

In addition to cell transplantation, ideas for "niche therapy" are being developed: altering vascular and glial signals so that the patient's own neural stem cells are activated and work more effectively. This requires precise biomarkers of response and rigorous testing due to the risk of side effects. [29]

Table 6. Clinical directions and status

Direction	Stage	Main challenges
Dopaminergic neuron replacement in Parkinson's disease	Phase 1, safety confirmed	Patient selection, long-term efficacy, immunosuppression
Neural stem cell implantation for spinal cord injury	Early phases, pilot episodes	Standards of procedure and rehabilitation, design of controlled trials
Personalized induced progenitors	Preparing for the clinic	Quality, immune compatibility, cost
Niche therapy	Preclinical and early approaches	Targeting accuracy, security
[30]

Risks, safety control and bioethics

The main risks of cellular interventions are tumorigenesis, immune reactions, and abnormal integration. Contamination with undifferentiated cells and incomplete genetic stability testing further increase the risk. Therefore, extensive tumor testing, long-term monitoring, and strict purification protocols are essential before clinical use. [31]

A separate area is tumor stem-like cells in gliomas, which exploit stem cell programs to grow and become resistant to therapy. Understanding their biology helps identify drug targets and simultaneously increases safety requirements for any brain transplants. Markers like CD133 and nestin are important for research, but are not "labeled" in routine clinical practice. [32]

Research ethics are defined by international guidelines. Updated recommendations from the International Society for Stem Cell Research outline standards for basic science and clinical translation, including risk assessment, informed consent, and oversight. In 2025, the society released a targeted update to its sections on stem cell-based models of embryonic development. [33]

The development of brain organoids has raised questions about the potential sensitivity and legal status of complex models. Expert reviews and policy papers offer a framework for responsible use without hindering innovation. For the clinic, this means increased attention to ethical oversight and public trust. [34]

Table 7. How to reduce the risks of cell therapies

Risk	Reduction measures
Tumor formation	Deep cleaning of products, tumor tests, long-term monitoring
Immune reactions	Selection of immunosuppressive regimens, monitoring, and flexible withdrawal protocols
Incorrect integration	Precise neurosurgical targeting, image guidance, step-by-step doses
Ethical issues	Compliance with international guidelines, independent oversight
[35]

What's important for practice right now

Even with cautious optimism, cell-based therapies for the nervous system remain an early clinical area. The greatest progress has been made in dopaminergic neuron replacement in Parkinson's disease, where early safety and signs of graft viability have been demonstrated. Other areas require larger, controlled trials with well-designed outcome measures. [36]

Patients and physicians should rely on centers that follow protocols rather than commercial offers without evidence. International guidelines emphasize the unacceptability of "promising clinics" and the importance of transparent trial registries. Verifying study registration and publications is a basic safety measure. [37]

In non-invasive recovery support, rehabilitation programs, education, and risk factor management remain relevant. For patients with spinal cord injury, combined approaches that combine cell therapy with rehabilitation and neuromodulation are promising, but their value needs to be confirmed in methodologically rigorous studies. [38]

For scientists and developers, production standardization, quality criteria, reproducibility, and comprehensive reporting remain priorities. This accelerates regulatory approval and reduces implementation costs. [39]

Table 8. Where the field is heading in the next 3-5 years

Vector	Target	Why is this important?
Long-term safety	Exclude hidden tumorigenesis and genomic instability	Basis for widespread implementation
Precise niches "in the cup"	Improve the maturation of desired precursors	Critical to efficiency
Combinations with rehabilitation and neuromodulation	Overcoming variability in functional outcomes	Increase clinical relevance
Ethical framework for organoids	Maintain the trust of society and scientists	Accelerate responsible research
[40]

Brief conclusion

Neural stem cells exist in humans, function in well-organized niches, and, based on current data, support limited but significant neurogenesis, particularly in the hippocampus. Their potential for restoration is real, but requires rigorous protocols and evidence of long-term efficacy and safety. The most mature clinical applications include replacement of dopaminergic neurons in Parkinson's disease and careful pilot implantation in spinal cord injury. Ethical standards and production quality are as critical components of progress as the cells themselves. [41]