Biology subjects

Park, I.-H.

Publications and source records attributed to Park, I.-H..

6 recordsLinked to original sources

bioRxiv2026

Dysregulation of Hippo Signaling Pathway as a Convergent Mechanism Underlying Choroid Plexus Defects in Bipolar Disorder

Bipolar disorder (BD) is a prevalent and highly heritable psychiatric condition. Developmental mechanisms are implicated but the specific molecular origins remain unclear. The choroid plexus (ChP), which regulates cerebrospinal fluid (CSF) and brain homeostasis, has been implicated in BD, but its role is poorly understood. Here, we identify aberrant expansion of ChP in human cortical (hCOs) and ChP organoids (hChPOs) derived from, and in vivo structural magnetic resonance imaging (sMRI) scans of, individuals with BD compared to healthy comparison individuals. Single-cell transcriptomics revealed a lineage bias toward ChP fate in BD hCOs, accompanied by structural enlargement observed in both BD hChPOs and ChP in sMRI scans from individuals with BD. Comprehensive transcriptomic profiling implicates early hyperactivation of the Hippo signaling pathway in neural progenitor cells as a convergent mechanism driving ChP overgrowth. Whole-genome and genome-wide association study analyses highlight recurrent genetic variants in Hippo regulators, including STK4 and YAP1, suggesting genetic priming. BD hChPOs exhibit disrupted epithelial junctions and altered in vitro CSF secretion. These findings position the ChP as a genetically and developmentally predisposed to pathology in BD and highlight organoids as a platform for translational discovery in diagnostics and therapeutics.

developmental biology↗

bioRxiv2025

Non-integrating direct reprogramming generates therapeutic endothelial cells with sustained vascular regeneration capacity enhanced by nanomatrix delivery

RationaleDirect reprogramming of fibroblasts into endothelial cells (rECs) using ETV2 shows promise for vascular regeneration. However, current approaches using integrating viral vectors pose clinical translation barriers, and poor long-term cell survival limits therapeutic efficacy. ObjectiveTo develop a clinically compatible method for generating rECs using non-integrating adenoviral ETV2 (Ad-ETV2) and enhance their engraftment and therapeutic efficacy through peptide amphiphile (PA) nanomatrix encapsulation. Methods and ResultsHuman dermal fibroblasts were reprogrammed using Ad-ETV2 and characterized by flow cytometry, RNA sequencing, and functional assays. Therapeutic efficacy was evaluated in murine hindlimb ischemia with or without PA-RGDS encapsulation over 12 months. Ad-ETV2 induced robust endothelial gene expression (CDH5, KDR, PECAM1) within 6 days, with 40-50% reprogramming efficiency. KDR+ Ad-rECs demonstrated functional endothelial properties including Ac-LDL uptake, tube formation, and exceptional proangiogenic factor secretion (200-fold higher HGF than HUVECs). RNA sequencing revealed rapid transcriptional reprogramming with fibroblast gene suppression and endothelial/angiogenic gene activation. In hindlimb ischemia, Ad-rECs significantly enhanced blood flow recovery and capillary density versus controls. Long-term analysis revealed sustained vascular contribution through three mechanisms: direct incorporation, perivascular support, and vessel guidance, persisting throughout 12 months--the longest reported follow-up for reprogrammed cells. PA-RGDS encapsulation markedly improved cell retention; while 75% of cells were lost by 3 months, retention stabilized thereafter with minimal additional loss through 12 months. ConclusionsAdenoviral ETV2 delivery enables efficient generation of clinically compatible rECs without genomic integration. These cells demonstrate potent and sustained therapeutic efficacy through multiple vascular regeneration mechanisms. PA-RGDS encapsulation significantly enhances long-term engraftment, establishing this combined approach as a promising platform for treating ischemic cardiovascular diseases.

cell biology↗

bioRxiv2024

Brainwaves Monitoring via Human Midbrain Organoids Microphysiological Analysis Platform: MAP

Understanding the development and pathogenesis of the human midbrain is critical for developing diagnostics and therapeutics for incurable neurological disorders including Parkinsons disease (PD)1-3. While organoid models are introduced to delineate midbrain-related pathogenesis based on experimental flexibility4-6, there is currently a lack of tools with high fidelity for tracing the long-term dynamics of intact brain networks-- an essential portrait of physiological states7,8. Here, we report a brain organoid microphysiological analysis platform (MAP) designed for long-term physiological development and in-situ real-time monitoring, akin to electroencephalogram (EEG), of midbrain organoids. We successfully achieved the on-chip homogeneous organogenesis of midbrain organoids and in-situ, non-disturbing electrophysiological tracking of the midbrain network activities. Throughout our long-term EEG monitoring via MAP, we captured the early-stage electrophysiological evolution of midbrain development, transitioning from discontinuous brief brainwave bursts to complex broadband activities. Furthermore, our midbrain organoid MAP facilitated the modeling and monitoring of neurotoxin-induced Parkinsonism, replicating the pathological dynamics of midbrain circuitry and exhibiting PD-like alterations in beta oscillation. We envision that the modeling and monitoring of brain organoid MAP will significantly enhance our understanding of human neurophysiology, neuropathogenesis, and drug discovery of neurodegenerative diseases.

bioengineering↗

bioRxiv2024

FOXA1 is required for ErbB2 expression and luminal differentiation in HER2-positive breast cancer

The function of the pioneer factor forkhead box A1 (FOXA1) in estrogen receptor (ER)-negative, human epidermal growth factor receptor 2 (HER2, encoded by the ERBB2 gene)-positive breast cancer represents a critical gap in our understanding of lineage identity in tumorigenesis. Here, we solve this enigma by addressing this question through the identification of an indispensable, co-dependent regulatory circuit formed between FOXA1 and the SAM pointed domain containing ETS-family transcription factor (SPDEF). Using integrative multi-omics analyses of patient tumors and experimental models, we demonstrate that this circuit functions as the master guardian of the HER2-positive luminal state. It executes this role via two distinct, essential mechanisms: it directly binds regulatory elements to drive high-level expression of the ERBB2 oncogene, and it simultaneously preserves epithelial identity by suppressing a latent program of epithelial-to-mesenchymal transition (EMT). Mechanistically, the FOXA1/SPDEF circuit promotes the expression of the transcriptional repressor TRPS1, which in turn antagonizes the pro-mesenchymal activity of the TEAD/YAP complex. Our findings define a central regulatory node that couples lineage fidelity to oncogenic output in HER2-positive cancer, revealing the FOXA1/SPDEF-TRPS1 axis as a critical determinant of tumor plasticity and a potential therapeutic target for overcoming resistance in HER2-positive breast cancer.

cancer biology↗

bioRxiv2022

Dyslexia associated gene, KIAA0319, regulates cell cycle during human neuroepithelium development

Reading Disability (RD), also known as dyslexia, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of RD is between 5% and 17%, and the heritability ranges from 44% to 75%. Genetic linkage analysis and genome-wide association studies (GWAS) have identified several genes and regulatory elements linked to RD and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. Association of KIAA0319 has been independently replicated in multiple independent studies and languages. Rodent models suggest that KIAA0319 is involved in neuronal migration, but its precise function is unknown. This studies aim to determine the mechanisms by which KIAA0319 affects reading and language performance. We hypothesize that KIAA0319 plays a critical role in neuronal development. RT-qPCR and quantitative immunofluorescence in the cortical neurons differentiated from H7 hESC show regulatory effects on proliferation and differentiation of neuronal progenitor cells. Knockdown of KIAA0319 expression promotes early exit from the neuroepithelial cell stage and drives cells into cell cycle arrested neuronal progenitor cell stage. This suggests that KIAA0319 act by regulating neurogenesis in the reading related centers of the brain by targeting the cell cycle of proliferative cells. This demonstrates how subtle changes in expression could affect an isolated trait such as reading without global brain effects.

developmental biology↗

bioRxiv2020

Scalable production of tissue-like vascularised liver organoids from human PSCs.

A lack of physiological parity between 2D cell culture and in vivo, has paved the way towards more organotypic models. Organoids exist for a number of tissues, including the liver. However, current approaches to generate hepatic organoids suffer drawbacks, including a reliance on extracellular matrices (ECM), the requirement to pattern in 2D culture, costly growth factors and a lack of cellular diversity, structure and organisation. Current hepatic organoid models are generally simplistic, composed of hepatocytes or cholangiocytes, which renders them less physiologically relevant when compared to native tissue. Here we aim to address these drawbacks. To address this, we have developed an approach that does not require 2D patterning, is ECM independent combined with small molecules to mimic embryonic liver development that produces massive quantities of liver like organoids. Using single-cell RNA sequencing and immunofluorescence we demonstrate a liver-like cellular repertoire, a higher order cellular complexity, presenting with vascular luminal structures, innervation and a population of resident macrophage - the Kupffer cells. The organoids exhibit key liver functions including drug metabolism, serum protein production, coagulation factor production, bilirubin uptake and urea synthesis. The organoids can be transplanted and maintained in mice producing human albumin long term. The organoids exhibit a complex cellular repertoire reflective of the organ, have de novo vascularization and innervation, enhanced function and maturity. This is a pre-requisite for a myriad of applications from cellular therapy, tissue engineering, drug toxicity assessment, disease modeling, to basic developmental biology.

cell biology↗