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‘Chronic lymphocytic leukemia can be predicted by lymphoid clonal hematopoiesis, but this is not the case for all patients. Here, the authors analyse mitochondrial heteroplasmy as a potential biomarker of disease.

Sergiu Pașca is a faculty member at Stanford University, where he is also the Uytengsu Director of the Stanford Brain Organogenesis Program. He is a pioneer in developing 3D brain-region-specific organoids, assembloids and cellular models of neuropsychiatric disease from stem cells.

Human pluripotent stem cells were used to develop dorsal and ventral forebrain 3D spheroids, which can be assembled to study interneuron migration and to derive a functionally integrated forebrain system with cortical interneurons and glutamatergic neurons.

Risk associated with genetically defined forms of autism spectrum disorder (ASD) can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing insight into the convergent impact of ASD genetic risk on human neurodevelopment.

Difficult questions will be raised as models of the human brain get closer to replicating its functions, explain Nita A. Farahany, Henry T. Greely and 15 colleagues.

Addition of an inexpensive, biocompatible polymer reduces spontaneous fusions of organoids in culture.

Cortical organoids derived from tetraploid human–chimpanzee fused induced pluripotent stem cells provide a platform for untangling unique molecular features of human brain development.

Neural differentiation and self-organization of hPSCs are induced by culture in suspension. Neural spheroids are then differentiated into dorsal or ventral forebrain spheroids that can be combined to obtain functionally integrated human assembloids.

The relationship between heteroplasmy and clonal hematopoiesis of indeterminate potential and its association with the incidence of myeloid neoplasms (MN) remains to be explored. Here, the authors suggest that heteroplasmy is a marker of clonal expansion and a significant risk factor for MN development.

A method for 3D differentiation of human pluripotent stem cells yields brain cortical spheroids with functional neurons and astrocytes. The spheroids can be sliced for imaging and electrophysiological studies.

A human ascending somatosensory assembloid model was developed, which integrates multiple organoids to simulate the spinothalamic pathway, demonstrating functional connectivity and responsiveness to stimuli and revealing insights into pain-related genetic mutations.

Gordon et al. use genome-wide unbiased approaches to show that human cerebral cortical organoids, when cultured for many months, start to resemble stages of postnatal brain development, with a timeline that parallels in vivo development.

This protocol combines pooled CRISPR–Cas9 screening with neural organoid and assembloid models and illustrates how it can be applied to map hundreds of disease genes onto cellular pathways and specific aspects of human neural development.

A new technique, in which forebrain-precursor cells are ablated from early-stage mouse embryos and replaced with embryonic stem cells, promises to facilitate our ability to study the central nervous system.

Two groups have grown self-organizing models of mouse embryos from stem cells in vitro. The models mimic mid-gestation embryos, providing an unparalleled opportunity to study early embryonic development.

Andersen, Thom and colleagues reveal the single-cell-resolution transcriptome of the midgestation human spinal cord and discover remarkable heterogeneity across and within cell types.

Antisense oligonucleotides effectively decrease the inclusion of exon  8A of CACNA1C in human cells both in vitro and in rodents transplanted with human brain organoids, and a single intrathecal administration rescued both calcium changes and in vivo dendrite morphology of patient neurons.

Electrical activity in neural organoids is captured with a device inspired by a paper-cutting art.

Assembloids are integrated with CRISPR screening to investigate the involvement of 425 neurodevelopmental disorder genes in human interneuron development, showing endoplasmic reticulum displacement before nuclear translocation and interference from LNPK deletion, resulting in abnormal migration.

Human stem cell-derived cortical organoids transplanted into rats mature and integrate into sensory and motivation circuits to influence behaviour.

A human stem cell–derived model helps to uncover neuronal phenotypes associated with genetic forms of neuropsychiatric disease.

Organoids representing the human striatum are generated and used to build circuits in cortico-striatal assembloids.

A human neural organoid cell atlas integrating 36 single-cell transcriptomic datasets shows cell types and states and estimates transcriptomic similarity between primary and organoid counterparts, showing potential to assess organoid fidelity and facilitate protocol development.

A protocol adapted to xeno- and feeder-free conditions is shown to generate reliable and consistent cortical brain organoids across differentiations and source stem cell lines, making it suitable for disease modeling and other applications.

The nomenclature for human multicellular models of nervous system development and disease, including organoids, assembloids and transplants, is discussed and a consensus framework is presented.

Nano-bio interfaces enable communication between synthetic materials and biological systems at the nanoscale, with their functionality shaped by material properties, surface chemistry and topography. This Review discusses the key considerations and methods for engineering nano-bio interfaces for bioelectrical signal detection and biochemical signal transduction.

Brain organoids derived from human iPSCs are used to study the effects of hypoxia on early cortical neurodevelopment and identify defects in specific human progenitor populations that likely contribute to encephalopathy of prematurity.

Bioprinting has potential in the biofabrication of three dimensional tissues, but is poorly suited to the manipulation of neural organoids. Here, the authors develop a bioprinting platform to allow the arrangement of organoids to form assembloids.

Timothy syndrome is a neurodevelopmental disease that includes autism-like features. Using iPS-derived neurons from individuals with Timothy syndrome, Ricardo Dolmetsch and his colleagues identify changes in cortical neuron fate and neurotransmitter expression that may begin to explain the neural mechanisms that underlie this disorder.

NeuroString, a tissue-like biological interface created by laser patterning of polyimide into a graphene/nanoparticle network embedded in an elastomer, is introduced, allowing in vivo real-time detection of neurotransmitters in the brain and gut.

Human pluripotent stem cell-derived in vitro models have potential as tools to study aspects of human brain development. Here, Heilshorn and colleagues review biomaterial-based approaches that may be integrated into these models in an effort to develop them further and better recapitulate neurodevelopmental processes.

Single-cell and bulk transcriptomics of adult human microglia from a population of individuals reveals activated states across several brain disorders and maps Alzheimer’s disease variants to microglia-enriched genes.

Human brain organoids are endowed with regional topography using engineered signaling centers.

Zika virus infection is associated with birth defects, including microcephaly, but also with disorders of peripheral nerves. Oh et al. use rodent and human cell models to explore how the virus affects the peripheral nervous system.

Stem cell–derived human motor neurons were used to investigate the cellular mechanisms underlying C9ORF72-related amyotrophic lateral sclerosis.

By integrating ongoing bioethical collaboration, neuroscientists can create a positive effect on their research and the knowledge it produces. To this end, we offer our experiences with an interdisciplinary model for the ethical advancement of a promising area of neuroscience — human neural organoid research.

The authors report that calcium channels with a mutation associated with Timothy syndrome cause activity-dependent dendrite retraction in rodent neurons and in induced pluripotent stem cell–derived neurons from individuals with Timothy syndrome. This retraction was independent of Ca permeation but was associated with activation of RhoA signaling.

The authors generate 3D brain organoids containing oligodendrocytes, astrocytes, and neurons derived from human pluripotent stem cells. These human oligodendrocytes are transcriptionally similar to primary cells and mature to myelinate axons.

The transplantation of human cortical organoids in rats enables maturation and integration of human neural cells that can engage with the host circuitry, providing a framework to study alterations in morphology and physiology of patient-derived tissue.

AAV vectors that efficiently transduce the mouse brain after intravenous injection are generated with a CRE-dependent selection system.

An international group of neuroscience researchers presents a framework for experimental designs for research using neural organoids and assembloids to study human development, evolution and disease.

Organoids are 3D cell culture systems that mimic the structural and functional characteristics of organs. In this Review, the authors discuss the biochemical and mechanical material properties relevant for organoid formation and highlight materials designed with the aim to establish organoid cultures as powerful research platforms.

A protocol is described for generating human brain assembloids and performing viral labeling and retrograde tracing, 3D live imaging of axon projection and optogenetics with calcium imaging and electrophysiological recordings to model neural circuits.

Rare genetic diseases frequently involve a neuropsychiatric component for which a defined framework of investigation will expedite our understanding for these diseases as a whole.