The rise of neural stem cells: From development to disease

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Fiona Doetsch (left) and Rebecca Matsas (right), guest editors of this special issue

The brain is a remarkably complex organ that arises during development from neural stem cells. Neural stem cells undergo self-renewing divisions to first expand their pool and then differentiate, either via intermediate progenitors or directly into neurons to form the developing brain. Glial cells, namely astrocytes and oligodendrocytes, are generated later in development. This sequential development is the result of precisely timed patterning and signaling that underlie proper brain formation.

Neural stem cells are also found in the adult brain, where they continue to generate neurons in certain regions throughout life. Adult neural stem cells reside in complex niches that provide diverse signals to maintain their quiescent state or activate them to divide. Long-range signals, including factors in the circulation, the cerebrospinal fluid, as well as neural circuits, are emerging as key modulators of adult neural stem cells, as are different physiological states (Chaker et al., 2024). Understanding the in vivo complexity of the niche is key to understand how stem cells contribute to brain plasticity, are affected by aging, how they can be induced to divide after injury in vivo and potentially repair the damaged brain, and how they can become dysregulated in different disease states.

It is an exciting time in the neural stem cell field. Breakthroughs are being made into fundamental mechanisms underlying stem cell self-renewal and differentiation. Novel technologies from single-cell multiomics to spatial approaches and computational advances are illuminating stem cell heterogeneity and enabling detailed molecular understanding of how chromatin architecture and epigenetic modifications underlie how stem cells sense and respond to different extrinsic signals. By incorporating evolutionary perspectives, new insights are being gleaned into the larger size and unique features of the human brain and what regulates intrinsic differences in developmental timing between species (Iwata and Vanderhaeghen, 2024; Moss et al., 2024).

In this special issue, review articles and primary articles touch on several of these themes, providing key insights from different systems, spanning from fish to humans. How neural progenitors decode stochastic spatiotemporal cues to differentiate into appropriate cell types is examined by Rajan et al. during olfactory neurogenesis in developing zebrafish. Spanou et al. investigate the role of the tumor suppressor promyelocytic leukemia protein in neural stem cell survival and differentiation. Epigenetic mechanisms are emerging as key players in brain development. Ebert et al. examine the role of different Ten-Eleven Translocation (TET) enzymatic activities in establishing neuronal and glial competence of neural stem cells, and Alammari et al. dissect how chromatin regulators cooperate to control neural stem cell maintenance and neurogenesis in the postnatal brain.

A key question is the extent and functional significance of stem cell heterogeneity. Stem cells are rare populations that exist in different states. Long-term imaging of stem cells in vivo now allows stem cell and progenitor dynamics to be followed over time and to understand how adult-generated neurons incorporate into neural circuits (reviewed by Mizoguchi et al.) Purification strategies and computational approaches are being developed to dissect tissue complexity and capture rare populations of cells. Cappuccio et al. use a digital sorting algorithm to identify genes in progenitor cells potentially implicated in neurological conditions. Apostolou et al. integrate and compare different single-cell datasets of adult neural stem cells, highlighting that different isolation approaches impact the neural stem cell state. Liu and Gao et al. define how combinations of oncogenes can generate glioma-like lines from purified human progenitors.

Thanou et al. investigate how chemotherapeutic agents affect the adult brain and can induce the ectopic migration of neuroblasts into other brain areas, and Verkerke et al. review how endogenous stem cells might potentially be harnessed for brain repair in Parkinson’s disease. Lokka et al. review the shared origins and interplay between ependymal cells and neural stem cells and highlight understudied bi-ciliated ependymal cells. Chen and Li et al. review adult hippocampal neurogenesis and its molecular regulation and potential therapeutic perspectives.

The generation and optimization of in vitro stem cell models has opened up new avenues in the study of human brain development and disease (Wu and Nowakowski 2025) (Figure 1). Two-dimensional neuronal cultures have been instrumental in this respect, while later, the addition of glial cells in co-culture systems, particularly astrocytes and/or microglia, has provided a more realistic environment for modeling the cell biology and pathology of the human nervous system. These models have proved to be of value not only for understanding neurodevelopmental/neuropsychiatric diseases but also for recapitulating age-related neurodegenerative pathologies and assisting in drug discovery (Antoniou et al., 2022). Byeon and Ferreccio et al. use disease modeling to uncover cilia length defects in 16p11.2 deletion and duplication in human induced pluripotent stem cell (iPSC)-derived neuronal progenitors and identify TAOK2 kinase as a regulator of cilia length.

Figure 1.

iPSC-derived human neural stem cells forming characteristic rosettes

Credit to the Matsas lab and the Human Embryonic and Induced Pluripotent Stem Cell Unit of the Hellenic Pasteur Institute, Athens, Greece.

The establishment of three-dimensional cultures in the form of brain organoids with distinct regional identities provides a cellular environment mimicking more closely the in vivo situation, while the generation of even more complex systems, such as assembloids comprising two or more structures, recapitulates inter-regional brain connectivity (Paşca et al., 2025). Mancinelli et al. review how human brain organoids are increasingly being used to model the emergence of spontaneous and evoked neural activity, and Scuderi et al. review recent advances in human brain organoids, brain-on-chip systems, and assembloids to explore key morphogens involved in neural patterning. Bruzelius et al. show the incorporation of human embryonic stem cell-derived somatostatin interneurons into forebrain organoids, allowing for the investigation of interneuron development and their roles in neurological disorders. To capture even greater complexity, brain organoids are increasingly being enriched with the incorporation of brain-resident microglia or peripheral immune cells and vascularized to improve nutrient delivery and mimic brain physiology more accurately. These vascularized brain organoids are created using various methods, including the use of microfluidic devices or transplantation to become integrated into the host brain.

These transformative technologies, positioned in an area between human stem cell and laboratory animal research, are nonetheless associated with important ethical considerations. These include sample procurement, informed consent from human participants, commercialization, regulatory policy, as well as issues related with brain organoids as they become increasingly complex, which engender the need for a mindful ethical framework with societal responsibility. International Society for Stem Cell Research (ISSCR) guidelines have recently been updated that address many of these key questions (https://www.isscr.org/guidelines). Cohn et al. present strategies from an interdisciplinary working group to enhance transparency and communication with research participant donors in brain organoid research, a perspective that has been less explored.

This special issue was developed in parallel with the 2025 ISSCR International Symposium in the beautiful and historical city of Athens, entitled “Neural Stem Cells: Capturing Complexity and Plasticity from the Cell to the Organism.” The Greek stem cell community embraced with enthusiasm this unique opportunity to participate, meet, and interact with global scientists while a public event was scheduled to inform about the potential of stem cell research and emerging therapies for neurodegenerative diseases. It is the first time that a special issue is being coupled to an ISSCR international scientific symposium. As part of this initiative, invited speakers contributed reviews, and some symposium speakers were selected from manuscripts submitted to the special issue, in addition to abstract-selected speakers. We thank all of the participants for a highly engaging and stimulating symposium and all authors for their contributions to this special issue.

Acknowledgments

Work in the authors’ laboratories is supported by Swiss National Science Foundation 310030_208009 (F.D.) and Hellenic Foundation for Research and Innovation project grant 1019 DiseasePHENOTarget (R.M).

Declaration of interests

The authors declare no competing interests.