Modeling Human Neural Development and Disease with iPSCs
An ISSCR Digital Webinar featuring ISSCR 2025 Poster Award Winners
Image: Cerebral organoid with streams of late-born migratory interneurons from Sakurako Nagumo Wong.
Program Description: Discover how human iPSC-derived models are advancing our understanding of neural development, disease mechanisms, and genetic variability in this webinar presented by ISSCR 2025 Poster Award Winners. This is a unique opportunity to learn from emerging leaders and stay at the forefront of stem cell science.
Moderators
Poster Award Winners & Presenters
Rachel Battaglia, PhD
The Broad Institute of MIT and Harvard, USA
Presentation Title: NEUREXIN1 KNOCKOUT IPSC-DERIVED NEURONS DISPLAY HETEROGENOUS TRANSCRIPTOMIC EFFECTS ACROSS DIFFERENT GENETIC BACKGROUNDS
From Ralda Nehme’s Lab
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Schizophrenia (SCZ) is a severe psychiatric disorder with a high amount of genetic heritability. Neurexin 1 (NRXN1) is a presynaptic cell adhesion gene linked to SCZ; however, individuals with copy number variants in NRXN1 display incredible phenotypic variability from being neurotypical to developing psychiatric or neurodevelopmental disorders, suggesting a contribution of genetic background. To study the influence of the same mutation in different genetic backgrounds, we developed “village editing” (CRISPR/Cas9 gene editing in a cell village format) and generated NRXN1 knockouts (KOs) in induced pluripotent stem cell (iPSC) lines from 15 donors with low, neutral, or high polygenic risk scores for SCZ. Using this method, we achieved high efficiency and recovered untargeted control clones as well as heterozygous (33.1%) and homozygous (28.4%) deletions in NRXN1 for most donors. We differentiated iPSCs to cortical excitatory neurons for 28 days with mouse glia and performed RNA sequencing to determine the effect of NRXN1 KO on neuron transcriptomes. We found that genetic background deeply influences gene expression changes in NRXN1 KO neurons. Ongoing studies are leveraging these tools to characterize NRXN1 function in neural cells, including examination of synaptic and other cellular phenotypes. In summary, we generated novel tools to examine NRXN1 function, demonstrate the importance of including multiple genetic backgrounds, and provide a framework for rapid and efficient development of similar tools to study gene functions in complex, polygenic disorders.
Yutong Wan
The University of Hong Kong, Hong Kong
Presentation Title: MODELING HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE IV (HSAN IV) USING HUMAN DRG ORGANOIDS DERIVED FROM PATIENT INDUCED PLURIPOTENT STEM CELLS
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Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV) is a rare autosomal genetic disorder characterized by Congenital Insensitivity to Pain with Anhidrosis. It is caused by mutations in the Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1) gene. While previous animal studies have revealed the significance of NTRK1 in nociceptive neuron formation in the dorsal root ganglia (DRG), its role in congenital sensory neuropathy and the underlying disease mechanisms in the human context are less explored. In this study, we successfully established human DRG organoids and remodelled HSAN IV disease using induced pluripotent stem cells (iPSCs) lines derived from an HSAN IV patient’s urine. The patient carries homozygous mutations, including a G deletion in one allele at exon 7 leading to early stop code, and a G to A alteration in the other allele at exon 16 that converts glutamic acid to lysine. To eliminate the genetic variations, we also generated isogenic control by correcting the patient’s mutation using CRISPR-based gene editing. By analysing different developmental stages of DRG organoids, we found that DRG organoids derived from HSAN IV patients underwent a lineage switching between sensory neurons and glial cells without affecting the neural crest stem cell population. During early neurogenesis, a marked reduction of sensory neurons expressing ISLET+ and BRN3A+ cells was detected. Additionally, DRG organoids derived from the patient exhibited few mature sensory markers, TRKA, TRKC, TRPV, and CGRP, and defective axonal outgrowth and extension Notably, gliogenesis was initiated prematurely, with a significant upregulation of FABP7. These findings suggest that NTRK1 mutations disrupt the balance of neuronal and glial differentiation in human DRG during development, which may contribute to sensory neuropathy in adults. Future studies will focus on uncovering the molecular mechanisms mediated by NTRK1 and identifying therapeutic targets to restore proper neuronal-glial differentiation signals in human DRG.
Sakurako Nagumo Wong, PhD
Institute of Molecular Biotechnology GmbH, Austria
Presentation Title: CEREBRAL ORGANOIDS MODEL POSTNATAL INTERNEURON MIGRATION OF THE HUMAN CORTEX
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Much of what is known about human cortical development has been derived from rodent models, due to the highly conserved neural types and processes. However, a unique feature of human brain development is the protracted period of neurogenesis and interneuron migration. In humans, recent findings in postmortem tissue of the Arc migratory stream, the arc-ACC, and the EC stream into the postnatal cortex have changed the dogma that cortical interneuron migration is complete before birth. These studies shed light on a prolonged stage of human brain development and a longer plasticity window for fine-tuning of the developing circuit with local inhibitory inputs. This also leaves a wider window for potential insults, leading to neurological disorders such as autism and epilepsy. Here we have derived an iPSC dorsal::ventral assembloid model with fusion at day 120 and analysis after up to 390 days of culture, to model the migration dynamics of this postnatal process. Interestingly, we observed after over 200 days that newly born migratory interneurons arrange themselves into connected chains that are surrounded by astrocytes, unlike the dispersed migration seen at earlier time points. These interneurons express caudal ganglionic eminence (CGE) markers and are born late, shown with EdU birth dating. Analysis by electron microscopy reveals an architecture essentially indistinguishable from what has been seen in early postnatal human brains. Using a combination of time-lapse imaging, mathematical modelling, and single cell spatial transcriptomics, we uncovered that this unique mode of migration requires both intrinsic cues from the late-born interneurons, as well as specific interactions between the interneurons and surrounding astrocytes for chain formation and migration. For the first time, our work reconstitutes events of human brain development that occur after birth, allowing a genetic and cell biological analysis of this important phenomenon.