Sang Hoon Kim, Yura Choi, Jihong Oh, Eui Yeon Lim, Jung Eun Lee, Eun-Ji Song, Young-Do Nam, Hojun Kim. Gut and Liver 2024;18:621-31. https://doi.org/10.5009/gnl230130

Autism spectrum disorder (ASD) is linked to ion channel dysfunction, including chloride voltage-gated channel-4 (CLCN4). We generated Clcn4 knockout (KO) mice by deleting exon 5 of chromosome 7 in the C57BL/6 mice. Clcn4 KO exhibited reduced social interaction and increased repetitive behaviors assessed using three-chamber and marble burying tests. Surprisingly, these symptoms were improved by Risperidone treatment, a drug commonly used to treat ASD. RNA sequencing data from mouse neural progenitor cells (mNPCs) showed that the genes regulating trans-synaptic signaling, transmembrane transport, and neuronal projection development were significantly decreased in Clcn4 knockdown (KD) cells compared to wild type (WT). Moreover, Risperidone treatment increased the genes related to the ion transmembrane transport, membrane potential, and neuron projection development in Clcn4 KD. Abnormalities in synaptic plasticity and dendritic spine formation were also observed in Clcn4 KO compared to WT. We observed that phosphorylation of SYNAPSIN, PSD95, ERK and CREB, as well as the expression of CDK5, were reduced in the brains of Clcn4 KO mice. In Clcn4 KO cortical neurons, the phosphorylation of SYNAPSIN and PSD95 expressions also decreased compared to WT, indicating disrupted synaptic function. Additionally, Sholl analysis revealed a reduction in dendritic branching and neuronal projection length in both mouse and human CLCN4 KD neurons. Finally, the decreased phosphorylation of SYNAPSIN and expression of PSD95 along with dendrite abnormalities were restored after Risperidone treatment. These data suggest that dendritic outgrowth and synapse remodeling may serve as endophenotypic targets for drug efficacy in ASD.

Corneal endothelial dysfunction is a leading cause of vision impairment globally, traditionally managed through donor-dependent keratoplasty procedures. However, limitations in donor tissue availability, surgical complexity, and long-term graft survival have prompted the development of cell-based regenerative therapies. Among these, corneal endothelial cells (CECs) injection therapy has emerged as a minimally invasive alternative, offering the potential to restore endothelial function. This review provides a comprehensive analysis of recent advances in bioengineering strategies for CECs therapy, including cell sourcing from donor tissue, pluripotent stem cells, and transdifferentiated somatic cells; optimization of culture conditions and substrates; and delivery protocols that enhance cell adhesion and survival. We further examine clinical trial outcomes and propose future directions for clinical translation. The convergence of cell biology, biomaterials engineering, and translational medicine positions CECs injection therapy as a transformative solution to corneal blindness.

Objective This study aims to investigate may moesin deficiency resulted in neurodevelopmental abnormalities caused by negative impact on synaptic signaling ultimately leading to synaptic structure and plasticity.Methods Behavioral assessments measured neurodevelopment (surface righting, negative geotaxis, cliff avoidance), anxiety (open field test, elevated plus maze test), and memory (passive avoidance test, Y-maze test) in moesin-knockout mice (KO) compared to wild-type mice (WT). Whole exome sequencing (WES) of brain (KO vs. WT) and analysis of synaptic proteins were performed to determine the disruption of signal pathways downstream of moesin. Risperidone, a therapeutic agent, was utilized to reverse the neurodevelopmental aberrance in moesin KO.Results Moesin-KO pups exhibited decrease in the surface righting ability on postnatal day 7 (p<0.05) and increase in time spent in the closed arms (p<0.01), showing increased anxiety-like behavior. WES revealed mutations in pathway aberration in neuron projection, actin filament-based processes, and neuronal migration in KO. Decreased cell viability (p<0.001) and expression of soluble NSF adapter protein 25 (SNAP25) (p<0.001) and postsynaptic density protein 95 (PSD95) (p<0.01) was observed in days in vitro 7 neurons. Downregulation of synaptic proteins, and altered phosphorylation levels of Synapsin I, mammalian uncoordinated 18 (MUNC18), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB) was observed in KO cortex and hippocampus. Risperidone reversed the memory impairment in the passive avoidance test and the spontaneous alternation percentage in the Y maze test. Risperidone also restored the reduced expression of PSD95 (p<0.01) and the phosphorylation of Synapsin at Ser605 (p<0.05) and Ser549 (p<0.001) in the cortex of moesin-KO.Conclusion Moesin deficiency leads to neurodevelopmental delay and memory decline, which may be caused through altered regulation in synaptic proteins and function.

High-dose lead (Pb) exposure is known to trigger neuroinflammation and glial activation; however, underlying the effects of chronic, low-level Pb exposure affects brain development remain poorly understood. In this study, we investigated whether exposure to a sub-threshold concentration of Pb (50 ppm in drinking water), resulting in blood Pb levels (3.6 ± 1.6 ng/dL) well below current international safety standards, can impair neurodevelopment in mice using an integrative multi-omic and morphological approach. Chronic early-life exposure led to significant behavioral abnormalities, including reduced locomotor activity, altered repetitive behaviors, and deficits in working memory. Morphological analyses revealed region-specific dendritic atrophy in hippocampal CA1 neurons, characterized by shortened and less-branched basal dendrites, consistent with impaired hippocampal circuitry. Integrated transcriptomic and epigenomic profiling identified coordinated hypermethylation and downregulation of neurodevelopmental genes such as Rpl26, and Ube2r2. These epigenetic changes converged on suppression of the PI3K/AKT/mTOR signaling axis, as evidenced by the reduced phosphorylation of PI3K, AKT, mTOR, and GSK-3β, alongside reduced expression of essential synaptic proteins (Synapsin I, PSD95, and TrkB). In parallel, the downregulation of NF-κB and COX-2 indicated that these molecular and behavioral abnormalities arose through a non-inflammatory mechanism distinct from classical Pb-induced gliosis. Together, our findings demonstrate that even trace Pb exposure can disrupt neurodevelopment through epigenetic repression and signaling dysregulation, resulting in lasting synaptic and cognitive deficits. These results highlight the exceptional vulnerability of the developing brain to environmental Pb levels and underscore the urgent need to re-evaluate current global safety thresholds to ensure neurodevelopmental protection.

Ocular surface inflammation is a major disruptor of corneal epithelial homeostasis and a key driver of limbal stem cell deficiency (LSCD). Limbal stem cells (LSCs), residing within the specialized limbal niche, maintain corneal transparency through continuous epithelial renewal and by preventing conjunctival encroachment onto the corneal surface. Chronic or severe inflammatory insults—stemming from systemic autoimmune disorders, ocular surface diseases, infections, trauma, or environmental stressors—can damage both LSCs and their microenvironment, ultimately leading to limbal insufficiency. This review synthesizes current insights into the mechanisms by which inflammation impairs LSC survival, including cytokine-mediated cytotoxicity, oxidative stress, immune cell infiltration, and disruption of essential signaling pathways such as Wnt, Notch, and BMP. The distinction between LSC depletion and LSC dysfunction is highlighted, as residual stem cells may persist even in clinically advanced disease and can regenerate the corneal surface once the inflammatory milieu is corrected. Clinical manifestations, staging systems, and diagnostic markers—including p63α, ABCG2, and additional emerging molecular indicators—are summarized to support accurate assessment of LSCD severity. Current therapeutic strategies, ranging from anti-inflammatory medical management to surgical approaches such as SLET, CLET, and allogeneic transplantation, are reviewed alongside evolving regenerative and cell-based therapies. By integrating mechanistic understanding with clinical implications, this review underscores the critical interplay between inflammation and limbal niche failure and emphasizes the importance of early recognition and targeted intervention to preserve or restore LSC function.