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The differentiation of neural stem cells (NSCs) into neurons is proposed to be critical in devising potential cell-based therapeutic strategies for central nervous system (CNS) diseases, however, the determination and prediction of differentiation is complex and not yet clearly established, especially at the early stage. We hypothesize that deep learning could extract minutiae from large-scale datasets, and present a deep neural network model for predictable reliable identification of NSCs fate. Remarkably, using only bright field images without artificial labelling, our model is surprisingly effective at identifying the differentiated cell types, even as early as 1 day of culture. Moreover, our approach showcases superior precision and robustness in designed independent test scenarios involving various inducers, including neurotrophins, hormones, small molecule compounds and even nanoparticles, suggesting excellent generalizability and applicability. We anticipate that our accurate and robust deep learning-based platform for NSCs differentiation identification will accelerate the progress of NSCs applications. The differentiation of neural stem cells (NSCs) into neurons is a critical part in devising potential cell-based therapeutic strategies for central nervous system diseases but NSCs fate determination and prediction is problematic. Here, the authors present a deep neural network model for predictable reliable identification of NSCs fate.

Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes throughout life, but the functions of OPCs are not limited to oligodendrogenesis. Here we show that OPCs contribute to thalamocortical presynapse elimination in the developing and adult mouse visual cortex. OPC-mediated synapse engulfment increases in response to sensory experience during neural circuit refinement. Our data suggest that OPCs may regulate synaptic connectivity in the brain independently of oligodendrogenesis. Oligodendrocyte precursor cells (OPCs) have functions beyond oligodendrogenesis. Here the authors show that OPCs can engulf thalamocortical presynapses in response to sensory experience in mice.

Neural stem cells (NSCs) generate new neurons throughout life in the mammalian brain. Adult-born neurons shape brain function, and endogenous NSCs could potentially be harnessed for brain repair. In this Review, focused on hippocampal neurogenesis in rodents, we highlight recent advances in the field based on novel technologies (including single-cell RNA sequencing, intravital imaging and functional observation of newborn cells in behaving mice) and characterize the distinct developmental steps from stem cell activation to the integration of newborn neurons into pre-existing circuits. Further, we review current knowledge of how levels of neurogenesis are regulated, discuss findings regarding survival and maturation of adult-born cells and describe how newborn neurons affect brain function. The evidence arguing for (and against) lifelong neurogenesis in the human hippocampus is briefly summarized. Finally, we provide an outlook of what is needed to improve our understanding of the mechanisms and functional consequences of adult neurogenesis and how the field may move towards more translational relevance in the context of acute and chronic neural injury and stem cell-based brain repair.In this Review, Denoth-Lippuner and Jessberger present recent insights into adult hippocampal neurogenesis in rodents — from stem cell activation to the integration of newborn neurons into pre-existing circuits — and describe how newborn neurons affect brain function.

Spinal cord injury remains a scientific and therapeutic challenge with great cost to individuals and society. The goal of research in this field is to find a means of restoring lost function. Recently we have seen considerable progress in understanding the injury process and the capacity of CNS neurons to regenerate, as well as innovations in stem cell biology. This presents an opportunity to develop effective transplantation strategies to provide new neural cells to promote the formation of new neuronal networks and functional connectivity. Past and ongoing clinical studies have demonstrated the safety of cell therapy, and preclinical research has used models of spinal cord injury to better elucidate the underlying mechanisms through which donor cells interact with the host and thus increase long-term efficacy. While a variety of cell therapies have been explored, we focus here on the use of neural progenitor cells obtained or derived from different sources to promote connectivity in sensory, motor and autonomic systems.There have been a number of recent advances in the use of transplanted cells to enable functional recovery in animal models of spinal cord injury. Fischer and colleagues review this work and describe the use of neural progenitor cell transplants to restore connectivity in key neural systems following spinal damage.

Environmental and behavioral factors have been shown, in experimental settings, to affect neurogenesis in the mouse brain. We found that the density of proliferating neural stem/progenitor cells (NSPCs) and of neuroblasts was significantly lower in the Subependymal Zone stem cell niche of lab mice when compared with mice and pine voles captured in the wild, with seasonal variation observed only in voles. Moreover, levels of proliferation and neurogenesis were found to decrease in proportion to the decrease in the numbers of chromosomes (from the typical 2n = 40 down to 2n = 26) caused by Robertsonian fusions. In contrast, oligodendroglial progenitors and microglial cells were unaffected by wildlife, seasons and chromosomal fusions. When NSPCs were grown in cultures no differences were detected, suggesting that environmental and genetic effects are mediated by non-cell-autonomous mechanisms. These “real-world” data provide a platform for the identification of systemic factors and genetic loci that control postnatal brain neurogenesis.

Cell-replacement therapies have long been an attractive prospect for treating Parkinson disease. However, the outcomes of fetal tissue-derived cell transplants in individuals with Parkinson disease have been variable, in part owing to the limitations of fetal tissue as a cell source, relating to its availability and the lack of possibility for standardization and to variation in methods. Advances in developmental and stem cell biology have allowed the development of cell-replacement therapies that comprise dopamine neurons derived from human pluripotent stem cells, which have several advantages over fetal cell-derived therapies. In this Review, we critically assess the potential trajectory of this line of translational and clinical research and address its possibilities and current limitations and the broader range of Parkinson disease features that dopamine cell replacement based on generating neurons from human pluripotent stem cells could effectively treat in the future.There has been considerable interest in cell-replacement strategies for the treatment of Parkinson disease. In this Review, Parmar, Grealish and Henchcliffe highlight some of the key developments in this field, with a focus on therapies based on dopamine neurons derived from human pluripotent stem cells.

Emerging evidence now indicates that mitochondria are central regulators of neural stem cell (NSC) fate decisions and are crucial for both neurodevelopment and adult neurogenesis, which in turn contribute to cognitive processes in the mature brain. Inherited mutations and accumulated damage to mitochondria over the course of ageing serve as key factors underlying cognitive defects in neurodevelopmental disorders and neurodegenerative diseases, respectively. In this Review, we explore the recent findings that implicate mitochondria as crucial regulators of NSC function and cognition. In this respect, mitochondria may serve as targets for stem-cell-based therapies and interventions for cognitive defects.

Key Points The choroid plexus (ChP) is a secretory tissue found in each of the brain ventricles, the main function of which is to produce cerebrospinal fluid (CSF). Although the ChP–CSF system is essential for proper development of the nervous system owing to fluid pressure within the ventricles as well as myriad CSF-borne signalling factors, it is nevertheless one of the most understudied areas of neurobiology. A highly organized tissue, the ChP consists of simple cuboidal epithelial cells surrounding a core of fenestrated capillaries and connective tissue. As the interface between peripheral circulation and the CNS, the ChP forms the blood–CSF barrier via tight junctions between adjacent epithelial cells to restrict free passage of solutes from blood into CSF, and vice versa. The ChP is present in chordates above the lancelet, and its development, which is classically categorized into four stages on the basis of its histological appearance, occurs in a stereotyped manner. Further, the order of ChP development seems to be conserved across species, with the hindbrain (fourth ventricle) ChP appearing first, followed by the bilateral appearance of the telencephalic (lateral ventricle) ChP, and the diencephalic (third ventricle) ChP appearing last. The cell-intrinsic and -extrinsic molecular mechanisms that regulate ChP development are just now being elucidated. Although ChP epithelial cells are derived from neuroepithelial progenitors, they are non-neural cells in their mature state, suggesting the need to suppress neural character in favour of a non-neural cell fate. Genetic fate-mapping studies have illustrated that cells contributing to the telencephalic ChP and hindbrain ChP exhibit lineage segregation in the mature tissues. Moreover, the ChPs are transcriptionally heterogeneous, a trait that appears to be evolutionarily conserved from mice to humans. Recent work in the field has identified several ChP-derived factors with important roles in the developing and adult brain. Importantly, the ChP epithelial cell secretome has been described, suggesting a role for a ventricle-specific, regionalized CSF in the developing brain. The health of the vertebrate brain is dependent on appropriate levels of cerebrospinal fluid (CSF), which is secreted by the choroid plexus (ChP). In this Review, Lehtinen and colleagues examine ChP structure and development and explore recently discovered functions of the ChP–CSF system. The choroid plexus (ChP) is the principal source of cerebrospinal fluid (CSF), which has accepted roles as a fluid cushion and a sink for nervous system waste in vertebrates. Various animal models have provided insights into how the ChP–CSF system develops and matures. In addition, recent studies have uncovered new, active roles for this dynamic system in the regulation of neural stem cells, critical periods and the overall health of the nervous system. Together, these findings have brought about a paradigm shift in our understanding of brain development and health, and have stimulated new initiatives for the treatment of neurological disease.

In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli. Long-term cultures of human brain organoids display a high degree of cellular diversity, mature spontaneous neuronal networks and are sensitive to light. Enlightening organoids Three-dimensional cellular models of the human brain, or organoids, enable the in vitro study of cerebral development and disease, but exactly which cells are generated and how much of the brain's complexity they recreate is undefined. To investigate in depth the nature of cells in human cerebral organoids differentiated from pluripotent stem cells, Paola Arlotta and colleagues carried out droplet-based single-cell expression analysis on cells isolated from over 30 organoids at developmental stages ranging from 3 to 9 months and beyond. They identify a wide diversity of neurons and progenitors and show that the more mature organoids formed dendritic spines as well as electrically active networks, which responded to light stimulation. The authors suggest that organoids may facilitate the study of circuit function using physiological sensory mechanisms. Elsewhere in this issue, Sergiu Paşca and colleagues show that re-assembling ventral and dorsal forebrain spheroids obtained separately in vitro allows the migration of human interneurons and the formation of functional synapses.

The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing. Exercise has positive effects on the brain during aging. Here the authors show that in mice, platelet-released exerkine PF4 mediates the effects of exercise on the brain.