A human striatal–midbrain assembloid model of alpha-synuclein propagation Hoang-Dai Tran, Min-Kyoung Shin, Xin Yi Yeo, Sangyong Jung, Muhammad Junaid, et al. Brain, 2026 Animal models of the pathology of Parkinson's disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cell (hPSC)-derived neural organoids have provided improved access to study PD aetiology. This study established a method to generate human striatal–midbrain assembloids (hSMAs) from hPSCs for modelling alpha-synuclein (α-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways. Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present, and the neurons, such as dopaminergic neurons and GABAergic neurons, were electrophysiologically active in the hSMAs. Development of hSMAs in the presence of increased α-syn from SNCA overexpression induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn was retrogradely transported from the striatal area to dopaminergic neurons of the midbrain area and exhibited α-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant α-syn aggregates, similar to the pathological form in human patients, accumulated in the midbrain area of hSMAs. Treatment with a protein aggregation inhibitor (Anle138b) and an autophagy inducer (rapamycin) reduced α-syn aggregation, indicating the potential of hSMAs for drug testing. This study established hSMAs as a novel platform for modelling PD, demonstrating α-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.
Repetitive transcranial magnetic stimulation suppresses glia-associated neuroinflammation and promotes peripheral nerve recovery in neuropathic pain Daniel Youngsuk Kim, Hye Ryeong Sim, Joo-Wan Choi, Jee In Choi, Xin Yi Yeo, et al. Frontiers in Immunology, 2026 Background Neuropathic pain (NP) is a chronic condition caused by peripheral nerve damage and is characterized by persistent neuroinflammation and limited treatment options. Repetitive transcranial magnetic stimulation (rTMS) has been reported to modulate neuroinflammation in the brain. However, it remains unclear whether rTMS also influences inflammatory responses in the spinal cord and peripheral nerve structures. Methods A rat NP model was established by unilateral sciatic nerve ligation, and the effects of rTMS were evaluated through behavioral testing and molecular, histological, and ultrastructural analyses of the spinal cord and sciatic nerve. Results NP induced thermal hyperalgesia and mechanical allodynia, whereas rTMS significantly alleviated these pain-related behaviors (p < 0.05). In the spinal cord, NP increased the expression of pro-inflammatory markers including CD40, CD86, ionized calcium-binding adapter molecule-1 (Iba-1), and transient receptor potential cation channel subfamily V member 1 (TRPV1) (p < 0.05 for TRPV1; p < 0.01 for the others). rTMS significantly attenuated the increases in CD86, Iba-1, and TRPV1 (p < 0.01 for Iba-1; p < 0.05 for the others), while CD40 showed a decreasing trend without statistical significance. In the sciatic nerve, NP also elevated glial and inflammatory markers (Iba-1, TRPV1, S100, and glial fibrillary acidic protein (GFAP), which were significantly reduced following rTMS treatment (p < 0.01 for S100; p < 0.05 for the others). Immunostaining confirmed a reduction in both the number and activation state of Iba-1(+) and GFAP(+) cells in the rTMS-treated group. Ultrastructural analysis demonstrated improved myelin integrity in the sciatic nerve after rTMS, including increased myelin thickness, higher myelinated axon density, and a reduced G-ratio. rTMS also mitigated NP-induced gastrocnemius muscle atrophy, as indicated by increased muscle mass and cross-sectional area (p < 0.01). rTMS was associated with changes in ERK and Akt signaling pathways that were reduced under NP conditions. Conclusion rTMS alleviates NP by suppressing glia-associated neuroinflammation in both the spinal cord and sciatic nerve and by promoting structural recovery of peripheral nerves. These findings support rTMS as a promising non-invasive therapeutic strategy for NP.
Human Pluripotent Stem Cell-Derived Skeletal Muscle Organoid Model of Aging-Induced Sarcopenia Seongjun Park, Min‐Kyoung Shin, Dong Seok Jeong, Xin Yi Yeo, Yeo Jin Kim, et al. Journal of Cachexia Sarcopenia and Muscle, 2025 BackgroundSarcopenia is defined by the age‐related loss of muscle mass and function, with an impaired regenerative capacity of satellite cells (SCs). Despite their recognized importance in muscle regeneration, human model‐based studies on SCs in sarcopenia are still lacking, limiting our understanding of their role in age‐related muscle loss. Here, we aimed to develop a sarcopenia model using human pluripotent stem cells (hPSCs)‐derived skeletal muscle organoids (hSkMOs) and prevent the sarcopenia progression by testosterone treatment.MethodsThe 3D hSkMOs were generated from hPSC and exhibited structurally and functionally mature muscle fibres and spinal‐derived neurons including motor neurons and interneurons. The proportion of muscle and the diameter of muscle fibres were assessed. To investigate the acute pro‐inflammatory response and intrinsic regenerative capacity of hSkMOs, we induced sarcopenia‐like conditions by TNF‐α treatment for 2 days and analysed. To model aging‐induced sarcopenia and investigate the preventive effect of testosterone, chronic TNF‐α treatment was applied, followed by testosterone administration. Histological, biochemical, molecular and electrophysiological analyses were conducted in various experiments.ResultWe employed a stepwise differentiation protocol from 2D paraxial mesodermal induction to 3D myogenic specification, concluding with a maturation culture system. We observed that the majority of cells were T/BRA‐ and TBX6‐positive (+) paraxial mesodermal progenitors (T/BRA+, 82.04%; TBX6+, 78.18%), whereas the neuromesodermal progenitors demonstrated a relatively low proportion (T/BRA+/SOX2+, 15.91%; TBX6+/SOX2+, 11.45%). Single‐nucleus RNA‐sequencing and extensive immunohistochemistry confirmed the presence of the myogenic lineage cell types (myogenic progenitors/SCs, myocytes, muscle fibres) and the neural lineage cell types (spinal‐derived interneurons, motor neurons, glial cells, Schwann cells). Additionally, the growth of MyHC+ muscle fibres reached twice the thickness on Day 100 compared to that on Day 50 (p < 0.0001). We subjected them to TNF‐α treatment and analysed. Western blot analysis confirmed that TNF‐α/NF‐κB pathway associated factors such as NF‐κB p65, IκB‐α and AKT were highly phosphorylated (p < 0.05, p < 0.001). The administration of testosterone increased the proportion of activated SCs (PAX7+/MYOD+, 7.97%; PAX7+/Ki67+, 7.03%) compared to the TNF‐α group (PAX7+/MYOD+, 2.29%; PAX7+/Ki67+, 2.07%, p < 0.001). The administration of testosterone increased the Cross‐Sectional‐Area (987.1 μm2) compared to the TNF‐α group (644.7 μm2, p < 0.01).ConclusionsWe successfully developed a hSkMOs to demonstrate the structural maturity of the skeletal muscle and its functional interaction with spinal‐derived interneurons and motor neurons. Furthermore, we demonstrated that our hSkMOs are useful for modelling aging‐induced sarcopenia and providing a valuable platform for testing therapeutic interventions.
Contemporary insights into neuroimmune interactions across development and aging Xin Yi Yeo, Yunseon Choi, Yeonhee Hong, Hyuk Nam Kwon, Sangyong Jung Frontiers in Neurology, 2025 Initially considered distinct systems with independent physiological functions, recent evidence highlights the crucial role of active crosstalk between the nervous and immune systems in regulating critical physiological and neurological processes and immunological homeostasis. The identification of a direct body-brain circuitry allowing the monitoring of peripheral inflammatory responses, a unique skull bone marrow source of immune cells to the central nervous system (CNS), and the physical interface of the blood-brain barrier with the meningeal system suggest direct intersystem interactions, which can be further modulated by the local tissue environment, allowing non-neurological factors to influence neurological outcomes and vice versa. While there is a recognized age-dependent decline in both neurological and immune system function, in part due to the natural accumulation of cellular defects and the development of chronic systemic inflammation, it is unclear if the pre-existing bidirectional feedback mechanisms between the neurological and peripheral immune system plays a role in shaping the system decline, beyond commonly investigated pathological conditions. In this review, we will explore the effect of aging on the bidirectional communication between the neurological and immunological systems and attempt to understand how the inevitable age-dependent alterations of the interaction may concurrently drive immunosenescence, normal neurological decline, and neuropathological progression.
NOTCH2NLC GGC intermediate repeat with serine induces hypermyelination and early Parkinson’s disease-like phenotypes in mice Haitao Tu, Xin Yi Yeo, Zhi-Wei Zhang, Wei Zhou, Jayne Yi Tan, et al. Molecular Neurodegeneration, 2024 Background The expansion of GGC repeats (typically exceeding 60 repeats) in the 5’ untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson’s disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored. Methods Here, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs. Results Our findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG, were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex. Conclusions Our in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs.
Plant-Based Shape Memory Cryogel for Hemorrhage Control J. Deng, Z. Zhao, X.Y. Yeo, C. Yang, J. Yang, et al. Advanced Materials, 2024 The escalating global demand for sustainable manufacturing, motivated by concerns over energy conservation and carbon footprints, encounters challenges due to insufficient renewable materials and arduous fabrication procedures to fulfill specific requirements in medical and healthcare systems. Here, biosafe pollen cryogel is engineered as effective hemostats without additional harmful crosslinkers to treat deep noncompressible wounds. A straightforward and low‐energy approach is involved in forming stable macroporous cryogel, benefiting from the unique micro‐hierarchical structures and chemical components of non‐allergenic plant pollen. It is demonstrated that the pollen cryogel exhibits rapid water/blood‐triggered shape‐memory properties within 2 s. Owing to their inherent nano/micro hierarchical structure and abundant chemical functional groups on the pollen surface, the pollen cryogel shows effective hemostatic performance in a mouse liver penetration model, which is easily removed after usage. Overall, the self‐crosslinking pollen cryogel in this work pioneers a framework of potential clinical applications for the first‐hand treatment on deep noncompressible wounds.
Polar Lipids Supplementation Enhances Basal Excitatory Synaptic Transmission in Primary Cortical Neuron Xin Yi Yeo, Dao Tam, Yunju Jo, Jung Eun Kim, Dongryeol Ryu, et al. Molecular Nutrition and Food Research, 2024 ScopePolar lipids, such as gangliosides and phospholipids, are fundamental structural components that play critical roles in the development and maturation of neurons in the brain. Recent evidence has demonstrated that dietary intakes of polar lipids in early life are associated with improved cognitive outcomes during infancy and adolescence. However, the specific mechanisms through which these lipids impact cognition remain unclear.Methods and resultsThis study examines the direct physiological impact of polar lipid supplementation, in the form of buttermilk powder, on primary cortical neuron growth and maturation. The changes are measured with postsynaptic current response recordings, immunohistochemical examination of functional synapse localization and numbers, and the biochemical quantification of receptors responsible for neuronal synaptic neurotransmission. Chronic exposure to polar lipids increases primary mouse cortical neuron basal excitatory synapse response strength attributed to enhanced dendritic complexity and an altered expression of the excitatory α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subunit 2 (GluR2).ConclusionThe present finding suggests that dietary polar lipids improve human cognition through an enhancement of neuronal maturation and/or function.
