Biology subjects

Yoon, S.-J.

Publications and source records attributed to Yoon, S.-J..

7 recordsLinked to original sources

bioRxiv2026

Human neuromodulatory assembloids to study serotonin signaling and disease

Neuromodulators influence critical functions of the developing human brain and regulate behavioral states. Dysfunction of neuromodulatory systems is often involved in neuropsychiatric disease and many drugs for these conditions act on these signaling pathways. Recent advances in stem cell biology have made it possible to derive a wide range of cells across the developing human nervous system in regionalized organoids and to functionally integrate them into assembloids, however they currently do not systematically incorporate neuromodulation. Here, we generated human midbrain-hindbrain organoids (hMHO) from human induced pluripotent stem (hiPS) cells and fused them with human cortical organoids (hCO) to form neuromodulatory assembloids (hNMA). We focus on serotonin (5-hydroxytryptamine, 5-HT) as one key neuromodulator and found characteristic gene expression patterns and electrophysiological properties of serotonergic neurons (5-HT neurons) in the hMHO. In hNMA, 5-HT neurons projected into hCO, released 5-HT and modulated cortical network activity. To explore the applicability of this system in human disease, we studied 22q11.2 deletion syndrome (22q11.2DS), a common microdeletion associated with high risk for neuropsychiatric disease and defects in 5-HT signaling. We found aberrant 5-HT dynamics in hNMA from patient hiPS cell lines that were rescued by administration of a selective serotonin reuptake inhibitor (SSRI). Taken together, hNMA can be used to study human 5-HT dynamics and uncover disease phenotypes which could facilitate therapeutic development.

neuroscience↗

bioRxiv2025

Human assembloid model of emergent neurotropic enteroviruses

Enteroviruses (EVs) are the leading cause of viral meningitis in children. Recent outbreaks of non-polio EVs, most notably EV-A71 and EV-D68, have been associated with a polio-like paralysis known as acute flaccid myelitis (AFM). The lack of relevant models that mimic the cellular and functional responses of these human-restricted pathogens has hampered the development of effective treatments. We have previously engineered human stem cell-derived assembloids that recapitulate the neuromuscular connections underlying muscle contractions by integrating human spinal cord/hindbrain organoids (hSpO) and human skeletal muscle. Here, we used organoids and assembloids to investigate polio and non-polio EV pathogenesis. Infection of assembloids with poliovirus (PV), EV-D68 and EV-A71 resulted in loss of muscle contraction for all three viruses, which could be prevented by treatment with an antiviral agent. Yet, despite the convergence on neuronal dysfunction, the cellular targets by which each virus acted differed. More specifically, single cell transcriptomic profiling uncovered divergent cell tropisms between the EVs, and live imaging experiments revealed different modes and kinetics of cell damage. Altogether, we describe a multi-cellular model that captures viral pathogenesis in a human and circuit-relevant context.

neuroscience↗

bioRxiv2024

Developmental convergence and divergence in human stem cell models of autism spectrum disorder

Two decades of genetic studies in autism spectrum disorder (ASD) have identified over a hundred genes harboring rare risk mutations. Despite this substantial heterogeneity, transcriptomic and epigenetic analyses have identified convergent patterns of dysregulation across ASD post-mortem brain tissue. To identify shared and distinct mutational mechanisms, we assembled the largest hiPS cell patient cohort to date, consisting of 70 hiPS cell lines after stringent quality control representing 8 ASD-associated mutations, idiopathic ASD, and 20 lines from non-affected controls. We used these hiPS lines to generate human cortical organoids (hCO), profiling by RNAseq at four distinct timepoints up to 100 days of in vitro differentiation. Early timepoints harbored the largest mutation-specific changes, but different genetic forms converged on shared transcriptional changes as development progressed. We identified a shared RNA and protein interaction network, which was enriched in ASD risk genes and predicted to drive the observed down-stream changes in gene expression. CRISPR-Cas9 screening of these candidate transcriptional regulators in induced human neural progenitors validated their downstream molecular convergent effects. These data illustrate how genetic risk can propagate via transcriptional regulation to impact convergently dysregulated pathways, providing new insight into the convergent impact of ASD genetic risk on human neurodevelopment.

neuroscience↗

bioRxiv2023

Delayed blood pressure recovery after exercise stress test is associated with autonomic dysfunction and pulse pressure in a middle-aged healthy group

BackgroundDelayed heart rate (HR) and blood pressure recovery after exercise test is known as the reliable indexes of autonomic dysfunction. Here we tried to evaluate the serial changes in various indicators during exercise test and correlations among them in a normotensive healthy middle-aged group. MethodsA total of 122 patients without hypertension or diabetes was enrolled (mean age, 55.6 {+/-} 11.0; male, 56.6 %; mean blood pressure, 124.8 {+/-} 16.6 / 81.5 {+/-} 9.6 mmHg). Treadmill test was performed for evaluation of chest pain. Patients with coronary artery disease, positive treadmill test result, left ventricular dysfunction or renal failure were excluded. Heart rate recovery was calculated by subtracting the HR in the first or second minute of recovery period from the HR of peak exercise (HRR1 or HRR2). Systolic blood pressure in the 4th minute of recovery stage (SBPR4) was used to show delayed blood pressure recovery. ResultsMetabolic equivalents (METs) and HR in stage 2 to 4 were significantly correlated with both HRR1 and HRR2. Multiple regression analysis of HRR revealed significant correlation of METs and SBPR4. SBPR4 was significantly correlated with both HRR1 and HRR2 (HRR1, r=-0.376, p<0.001; HRR2, r=-0.244, p=0.008). SBPR4 revealed significant correlation with SBP in the baseline to stage 3 and pulse pressure (r=0.406, p<0.001). ConclusionsDelayed BP recovery after peak exercise test revealed significant association with autonomic dysfunction and pulse pressure in normotensive middle-aged healthy group. It can be a simple and useful marker of autonomic dysfunction and arterial stiffness.

neuroscience↗

bioRxiv2021

Landscape of human spinal cord cell type diversity at midgestation

Understanding spinal cord generation and assembly is essential to elucidate how motor behavior is controlled and how disorders arise. The cellular landscape of the human spinal cord remains, however, insufficiently explored. Here, we profiled the midgestation human spinal cord with single cell-resolution and discovered, even at this fetal stage, remarkable heterogeneity across and within cell types. Glia displayed diversity related to positional identity along the dorso-ventral and rostro-caudal axes, while astrocytes with specialized transcriptional programs mapped onto distinct histological domains. We discovered a surprisingly early diversification of alpha () and gamma ({gamma}) motor neurons that control and modulate contraction of muscle fibers, which was suggestive of accelerated developmental timing in human spinal cord compared to rodents. Together with mapping of disease-related genes, this transcriptional profile of the developing human spinal cord opens new avenues for interrogating the cellular basis of motor control and related disorders in humans.

neuroscience↗

bioRxiv2020

MicroRNA arm switching regulated by uridylation

Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may alter depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or "arm switching") remain elusive. Here we find mir-324 as one of the strongly regulated miRNAs by arm switching, and identify terminal uridylyl transferases TUT4 and TUT7 as the key regulators. Uridylation of pre-mir-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus, from which the 3' strand (3p) is selected instead of the 5' strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated while the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.

molecular biology↗

bioRxiv2018

Pseudomonas syringae evades phagocytosis in animal cells through type III effector-mediated inhibition of the LIM kinase-cofilin system

Certain animal and plant pathogenic bacteria have developed virulence factors (including effector proteins) that enable them to overcome host immunity. A plant pathogen, Pseudomonas syringae pv. tomato (Pto), secretes a large repertoire of effectors into plant cells via a type III secretory apparatus, thereby suppressing plant immunity. Here, we show that exposure to Pto caused sepsis in mice. Surprisingly, the effector HopQ1 disrupted phagocytosis by inhibiting actin rearrangement via a direct interaction with the LIM domain of the animal target protein LIM kinase, a key regulator of actin polymerization. The results provide new insights into cross-kingdom pathogenicity of bacteria. The current studies demonstrate that certain plant pathogenic bacteria such as Pto can be fatal in animals due to cross-kingdom host immune suppression.

microbiology↗