Biology subjects

Tchieu, J.

Publications and source records attributed to Tchieu, J..

12 recordsLinked to original sources

bioRxiv2026

Engineering human myelin microphysiological systems for testing patient treatment response in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, demyelination, and neurodegeneration, associated with a complex interplay between the innate and adaptive immune systems. Currently, no cure is available for MS, and personalized disease-modifying treatment remains largely limited, partially due to the lack of preclinical human models that can faithfully recapitulate disease pathology and evaluate treatment responses at the individual-patient level. Here, we report a human myelin microphysiological system (myelin MPS) platform that recaptures disease phenotype and treatment response for testing patient treatment response. By culturing neural organoids on 3D-printed devices containing directional microfibers, followed by coculture with oligodendrocyte progenitor cells, 96 myelin MPS models can be generated within a conventional well plate. Using this myelin MPS platform, autologous T cells and monocytes from MS patients induced substantially greater demyelination than those from healthy donors, accompanied by expansion of proinflammatory T-cell subsets and increased myelin uptake by monocytes/macrophages after coculture with these healthy myelinating neural tissues. Integration of imaging and flow-cytometric features distinguished healthy-donor, untreated-MS, responder, and nonresponder profiles following treatment with prednisone, glatiramer acetate, interferon {beta}-1a, or dimethyl fumarate. Thus, the myelin MPS platform provides a scalable, human pathophysiology-relevant platform for functional phenotyping and individualized treatment-response evaluation in MS.

bioengineering↗

bioRxiv2026

Brain organoid computing for robotic decision-making

Biomimicry has inspired the evolution of robotics toward greater autonomy, adaptability, and symbiosis with humans and dynamic environments. However, current robotic systems still face major challenges in recapitulating the high-efficiency decision-making capabilities of the human brain under complex and dynamic conditions. Here, we present Brainobot, a biohybrid robotic system that establishes a brain organoid controller as a high-level robotic decision-making layer for closed-loop embodiment. By leveraging brain organoid reservoir computing, Brainobot interacts with dynamic environments by receiving and processing sensory inputs and generating motor actions. As a proof-of-concept demonstration, Brainobot is implemented in a humanoid robotic system to perform real-world tasks, including object grasping and laser chasing. Interestingly, Brainobot exhibits unique features, including cross-task adaptivity, high computing efficiency, and low energy consumption. Thus, our approach may provide insights for advancing robotic embodiment and understanding biological decision-making.

bioengineering↗

bioRxiv2026

Selective vulnerability of excitatory cortical neurons to ZMYND11 loss reveals cell-type-specific mechanisms of neurodevelopmental disorder risk

Excitation/inhibition (E:I) imbalance is a convergent mechanism in neurodevelopmental disorders (NDDs), yet whether NDD risk genes disrupt excitatory and inhibitory neurons through shared or distinct molecular programs remains poorly understood. Using human pluripotent stem cell-derived cortical projection and medial ganglionic eminence-like inhibitory neurons, we show that loss-of-function mutations in the chromatin reader ZMYND11 produce cell-type-selective vulnerability in cortical excitatory neurons. ZMYND11-deficient excitatory neurons exhibit hyperexcitability accompanied by de-repression of BMP signaling, dysregulation of glutamate receptor expression, and a shift toward non-brain splicing isoforms, whereas these molecular signatures are largely absent in ZMYND11-deficient inhibitory neurons. This cell-type selectivity is associated with differential upregulation of RBFOX family splicing regulators. Structure-function analysis reveals that MYND domain is required for normal progenitor dynamics and neuronal excitability. Together, these findings indicate that E:I imbalance in ZMYND11-associated NDD arises primarily from cell-type-selective vulnerability of excitatory cortical projection neurons and identify MYND domain as a critical determinant of neuronal function. HighlightsO_LIZMYND11-deficient excitatory neurons (ExNs) show hyperexcitability. C_LIO_LIAltered BMP signaling & glutamate receptor levels are implicated in mutant ExNs. C_LIO_LIInhibitory neurons show attenuated response to ZMYND11 loss. C_LIO_LIThe MYND domain in ZMYND11 is a critical regulator of neuronal excitability. C_LI

neuroscience↗

bioRxiv2025

Dose-dependent NFI regulation of progenitor lifespan and output underlying human neocortical malformation

Nuclear Factor I (NFI) misexpressions in humans are associated with severe brain malformations, yet the underlying mechanisms remain poorly understood. Here we show that NFIs regulate the broad lineage progression and lifespan of radial glial progenitors (RGPs), and consequently neocortical development in a dose-dependent manner. Human cerebral organoids carrying patient-mimicking NFI mutations exhibit expression level-dependent bidirectional impairments in RGP temporal development, coinciding with patient phenotypes. In mouse models, selective removal of NFIs leads to a dramatic protraction of RGP lineage progression and lifespan, excessive progeny output, and neocortical overgrowth and abnormal folding, whereas overexpression of NFIs accelerates RGP lineage progression, resulting in developmental stage-dependent precocious productions of diverse neural progenies. Moreover, NFIs exhibit a positive auto-regulation and progressive increase in expression, and regulate distinct temporal-specific targets underlying RGP lineage progression. These results suggest that NFIs act as evolutionarily conserved key global temporal regulators of RGP lineage progression and neocortical development. HIGHLIGHTSO_LINFIs affect human RGP temporal development coinciding with patient phenotypes. C_LIO_LINFI removal protracts RGP lineage progression and lifespan with excessive progeny output. C_LIO_LINFI overexpression accelerates RGP lineage progression with precocious progeny output. C_LIO_LINFIs regulate distinct temporal-specific targets underlying RGP lineage progression. C_LI

neuroscience↗

bioRxiv2025

Patient-Specific Midbrain Organoids with CRISPR Correction Reveal Disease Mechanisms and Enable Therapeutic Evaluation in Neuronopathic Gaucher Disease

Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by GBA1 mutations, leading to defective acid {beta}-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells (hiPSCs) of nGD patients with GBA1L444P/P415R and GBA1L444P/RecNcil mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology. GBA1 mutation correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of GBA1 mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unravelling disease mechanisms and accelerating the discovery of therapies for patients with nGD.

neuroscience↗

bioRxiv2024

m6A-mediated epi-transcriptomic dysregulation underlies synaptic dysfunction in fragile X syndrome

Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and loss of the FMRP protein. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP is known to bind to and regulate the stability of m6A-containing transcripts. However, how loss of FMRP impacts on transcriptome-wide m6A modifications in FXS patients remains unknown. To answer this question, we generated cortical neurons differentiated from induced pluripotent stem cells (iPSC) derived from healthy subjects and FXS patients. In electrophysiology recordings, we validated that synaptic and neuronal network defects in iPSC-derived FXS neurons corresponded to the clinical EEG data of the patients from which the corresponding iPSC line was derived. In analysis of transcriptome-wide methylation, we show that FMRP deficiency led to increased translation of m6A writers, resulting in hypermethylation that primarily affecting synapse-associated transcripts and increased mRNA decay. Conversely, in the presence of an m6A writer inhibitor, synaptic defects in FXS neurons were rescued. Taken together, our findings uncover that an FMRP-dependent epi-transcriptomic mechanism contributes to FXS pathogenesis by disrupting m6A modifications in FXS, suggesting a promising avenue for m6A- targeted therapies.

neuroscience↗

bioRxiv2024

ZMYND11 Functions in Bimodal Regulation of Latent Genes and Brain-like Splicing to Safeguard Corticogenesis

Despite the litany of pathogenic variants linked to neurodevelopmental disorders (NDD) including autism (ASD) and intellectual disability1,2, our understanding of the underlying mechanisms caused by risk genes remain unclear. Here, we leveraged a human pluripotent stem cell model to uncover the neurodevelopmental consequences of mutations in ZMYND11, a newly implicated risk gene3,4. ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor5,6. Our findings reveal that ZMYND11-deficient cortical neural stem cells showed upregulation of latent developmental pathways, impairing progenitor and neuron production. In addition to its role on histones, ZMYND11 controls a brain-specific isoform switch involving the splicing regulator RBFOX2. Extending our findings to other chromatin-related ASD risk factors revealed similar developmental pathway activation and splicing dysregulation, partially rescuable through ZMYND11s regulatory functions.

neuroscience↗

bioRxiv2024

Vascular network-inspired diffusible scaffolds for engineering functional neural organoids

Organoids, three-dimensional in vitro organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present Vascular network-Inspired Diffusible (VID) scaffolds to fully recapture the benefits of physiological diffusion physics for generating functional organoids and phenotyping their drug response. In a proof-of-concept application, the VID scaffolds, 3D-printed meshed tubular channel networks, support the successful generation of engineered human midbrain organoids almost without necrosis and hypoxia in commonly used well-plates. Compared to conventional organoids, these engineered organoids develop with more physiologically relevant features and functions including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared to conventional organoids with significant diffusion limits. Combining these unique scaffolds and engineered organoids may provide insights for organoid development and therapeutic innovation.

bioengineering↗

bioRxiv2024

Deciphering Endothelial and Mesenchymal Organ Specification in Vascularized Lung and Intestinal Organoids

To investigate the co-development of vasculature, mesenchyme, and epithelium crucial for organogenesis and the acquisition of organ-specific characteristics, we constructed a human pluripotent stem cell-derived organoid system comprising lung or intestinal epithelium surrounded by organotypic mesenchyme and vasculature. We demonstrated the pivotal role of co-differentiating mesoderm and endoderm via precise BMP regulation in generating multilineage organoids and gut tube patterning. Single-cell RNA-seq analysis revealed organ specificity in endothelium and mesenchyme, and uncovered key ligands driving endothelial specification in the lung (e.g., WNT2B and Semaphorins) or intestine (e.g., GDF15). Upon transplantation under the kidney capsule in mice, these organoids further matured and developed perfusable human-specific sub-epithelial capillaries. Additionally, our model recapitulated the abnormal endothelial-epithelial crosstalk in patients with FOXF1 deletion or mutations. Multilineage organoids provide a unique platform to study developmental cues guiding endothelial and mesenchymal cell fate determination, and investigate intricate cell-cell communications in human organogenesis and disease. HighlightsO_LIBMP signaling fine-tunes the co-differentiation of mesoderm and endoderm. C_LIO_LIThe cellular composition in multilineage organoids resembles that of human fetal organs. C_LIO_LIMesenchyme and endothelium co-developed within the organoids adopt organ-specific characteristics. C_LIO_LIMultilineage organoids recapitulate abnormal endothelial-epithelial crosstalk in FOXF1-associated disorders. C_LI

developmental biology↗

bioRxiv2023

Suppression of ferroptosis by vitamin A or antioxidants is essential for neuronal development

Development of functional neurons is a complex orchestration of several signaling pathways controlling cell proliferation, differentiation, and homeostasis1. However, details about the involved factors are not fully understood. The balance of antioxidants and vitamins is important for neuronal survival, synaptic plasticity, and early neuronal development; thus, we hypothesized that ferroptosis--a lipid peroxidation dependent cell death modality that is inhibited by antioxidanats2,3--needs to be suppressed to gain neurons. Our study shows that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids. Intriguingly, impaired neuronal development in conditions lacking antioxidants can be fully restored when ferroptosis is specifically inhibited by ferrostatin-1, or neuronal differentiation occurs in the presence of sufficient amounts of vitamin A. Mechanistically, vitamin A activates the heterodimeric nuclear receptor complex Retinoic Acid Receptor (RAR)/Retinoid X Receptor (RXR)4, which upregulates expression of the ferroptosis regulators GPX4, FSP1, GCH1, and ACSL3, amongst others. Therefore, our study reveals that above a certain threshold, vitamin A increases expression of essential cellular gatekeepers of lipid peroxidation. This study uncovers a critical process during early neuronal development, where suppression of ferroptosis by radical-trapping antioxidants or vitamin A is required to obtain maturing neurons and proper laminar organization in cortical organoids.

cell biology↗

bioRxiv2023

Brain Organoid Computing for Artificial Intelligence

Brain-inspired hardware emulates the structure and working principles of a biological brain and may address the hardware bottleneck for fast-growing artificial intelligence (AI). Current brain-inspired silicon chips are promising but still limit their power to fully mimic brain function for AI computing. Here, we develop Brainoware, living AI hardware that harnesses the computation power of 3D biological neural networks in a brain organoid. Brain-like 3D in vitro cultures compute by receiving and sending information via a multielectrode array. Applying spatiotemporal electrical stimulation, this approach not only exhibits nonlinear dynamics and fading memory properties but also learns from training data. Further experiments demonstrate real-world applications in solving non-linear equations. This approach may provide new insights into AI hardware.

bioengineering↗

bioRxiv2022

Deriving Schwann Cells from hPSCs Enables Disease Modeling and Drug Discovery for Diabetic Peripheral Neuropathy

Schwann cells (SCs) are the myelinating and non-myelinating glia of the peripheral nervous system (PNS) and are essential for its function. Defects in SCs are associated with many PNS disorders including diabetic peripheral neuropathy (DPN), a condition affecting millions of patients. Here we present a strategy for deriving and purifying SCs from human pluripotent stem cells (hPSCs). The scalable cultures of SCs allow basic and translational applications such as high-resolution molecular and functional characterization, developmental studies, modeling and mechanistic understanding of SC diseases and drug discovery. Our hPSC-derived SCs recapitulate the key molecular features of primary SCs and are capable of engrafting efficiently and producing myelin in injured sciatic nerves in rats. We further established an hPSC-based in vitro model of DPN that revealed the selective vulnerability of human SCs to hyperglycemia-induced cytotoxicity. We established a high-throughput screening system that identified a candidate drug that counteracts glucose-mediated cytotoxicity in SCs and normalizes glucose-induced transcriptional and metabolic abnormalities in SCs. Treatment of hyperglycemic mice with this drug candidate rescues sensory function, prevents SC death, and counteracts myelin damage in sciatic nerves suggesting considerable potential as a novel treatment for DPN.

developmental biology↗