Jihye Yun

All Publications

• IGFBP2 Mediates Human iPSC-Cardiomyocyte Proliferation in a Cellular Contact-Dependent Manner. Circulation research Lee, S., Heinrich, P., Lee, D., Kang, Y., Robinson, H., Humphrey, S. J., Yun, J., Goodyer, W. R., Buikema, J. W., Paik, D. T., Galdos, F. X., Kim, B., Belbachir, N., Min, S., Cho, S. W., Lee, J., Moretti, A., Wu, J. C., Hudson, J., Wu, S. M. 2025

  Abstract

  Induction of cardiomyocyte proliferation in situ represents a promising strategy for myocardial regeneration following injury. However, cardiomyocytes possess intrinsic inhibitory mechanisms that attenuate pro-proliferative signaling and constrain their expansion. We hypothesized that cell-cell contact is a key suppressor of cardiomyocyte proliferation. We aimed to delineate the underlying molecular pathways to enable sustained proliferation in 3-dimensional contexts.Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured at varying plating densities to examine the impact of cell-cell contact on cell cycle activity. Phosphoproteomic profiling was performed in sparse versus dense cultures to identify signaling alterations. Conditioned media from sparse cultures were interrogated using a human growth factor array to identify secreted pro-proliferative factors.hiPSC-CM proliferation increased proportionally with plating density until intercellular contacts were established, at which point proliferation was suppressed. Dense cultures exhibited enhanced adherens junction assembly, sarcomeric organization, and contractile function. Increased cell-cell contact in dense conditions attenuated nuclear translocation of β-catenin and reduced TCF/LEF transcriptional activity, providing a mechanistic basis for the reduced hiPSC-CM proliferation. Disruption of adherens junctions or sarcomere assembly via siRNA-mediated knockdown of N-cadherin or α-actinin, respectively, resulted in increased cell cycle activation of hiPSC-CMs, but this was not sufficient to drive division of hiPSC-CMs. Additional screening for putative secreted growth factors in the conditioned media from sparsely plated hiPSC-CMs revealed the enrichment of IGFBP2, which was sufficient to drive hiPSC-CM division in the presence of cell-cell contact in 3-dimensional constructs.Our findings demonstrate that cell-cell contact inhibits hiPSC-CM proliferation through adherens junction formation, sarcomeric assembly, and reduced IGFBP2 secretion. Importantly, exogenous supplementation of IGFBP2 can overcome cell contact-mediated inhibition of hiPSC-CM proliferation and facilitate the growth of 3-dimensional cardiac tissue. These insights provide valuable implications for advancing cardiac tissue engineering and regenerative therapies.

  View details for DOI 10.1161/CIRCRESAHA.125.326522

  View details for PubMedID 41031396

• Transcriptome and epigenome dynamics of the clonal heterogeneity of human induced pluripotent stem cells for cardiac differentiation CELLULAR AND MOLECULAR LIFE SCIENCES Yun, J., So, J., Jeong, S., Jang, J., Han, S., Jeon, J., Lee, K., Jang, H., Lee, J. 2024; 82 (1): 2

  Abstract

  Human induced pluripotent stem cells (hiPSCs) generate multiple clones with inherent heterogeneity, leading to variations in their differentiation capacity. Previous studies have primarily addressed line-to-line variations in differentiation capacity, leaving a gap in the comprehensive understanding of clonal heterogeneity. Here, we aimed to profile the heterogeneity of hiPSC clones and identify predictive biomarkers for cardiomyocyte (CM) differentiation capacity by integrating transcriptomic, epigenomic, endogenous retroelement, and protein kinase phosphorylation profiles. We generated multiple clones from a single donor and validated that these clones exhibited comparable levels of pluripotency markers. The clones were classified into two groups based on their differentiation efficiency to CMs-productive clone (PC) and non-productive clone (NPC). We performed RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with sequencing (ATAC-seq). NPC was enriched in vasculogenesis and cell adhesion, accompanied by elevated levels of phosphorylated ERK1/2. Conversely, PC exhibited enrichment in embryonic organ development and transcription factor activation, accompanied by increased chromatin accessibility near transcription start site (TSS) regions. Integrative analysis of RNA-seq and ATAC-seq revealed 14 candidate genes correlated with cardiac differentiation potential. Notably, TEK and SDR42E1 were upregulated in NPC. Our integrative profiles enhance the understanding of clonal heterogeneity and highlight two novel biomarkers associated with CM differentiation. This insight may facilitate the identification of suboptimal hiPSC clones, thereby mitigating adverse outcomes in clinical applications.

  View details for DOI 10.1007/s00018-024-05493-9

  View details for Web of Science ID 001381918800001

  View details for PubMedID 39661125

  View details for PubMedCentralID PMC11635083

• PIV-MyoMonitor: an accessible particle image velocimetry-based software tool for advanced contractility assessment of cardiac organoids FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY Lee, H., Kim, B., Yun, J., Bae, J., Park, S., Jeon, J., Jang, H., Lee, J., Lee, S. 2024; 12: 1367141

  Abstract

  Induced pluripotent stem cell (iPSC)-derived cardiac organoids offer a versatile platform for personalized cardiac toxicity assessment, drug screening, disease modeling, and regenerative therapies. While previous image-based contractility analysis techniques allowed the assessment of contractility of two-dimensional cardiac models, they face limitations, including encountering high noise levels when applied to three-dimensional organoid models and requiring expensive equipment. Additionally, they offer fewer functional parameters compared to commercial software. To address these challenges, we developed an open-source, particle image velocimetry-based software (PIV-MyoMonitor) and demonstrated its capacity for accurate contractility analysis in both two- and three-dimensional cardiac models using standard lab equipment. Comparisons with four other open-source software programs highlighted the capability of PIV-MyoMonitor for more comprehensive quantitative analysis, providing 22 functional parameters and enhanced video outputs. We showcased its applicability in drug screening by characterizing the response of cardiac organoids to a known isotropic drug, isoprenaline. In sum, PIV-MyoMonitor enables reliable contractility assessment across various cardiac models without costly equipment or software. We believe this software will benefit a broader scientific community.

  View details for DOI 10.3389/fbioe.2024.1367141

  View details for Web of Science ID 001190751400001

  View details for PubMedID 38532875

  View details for PubMedCentralID PMC10964252

• Morolic Acid 3-<i>O</i>-Caffeate Inhibits Adipogenesis by Regulating Epigenetic Gene Expression MOLECULES Chae, S., Yi, S., Nam, K., Park, K., Yun, J., Kim, K., Lee, J., Han, J. 2020; 25 (24)

  Abstract

  Obesity causes a wide range of metabolic diseases including diabetes, cardiovascular disease, and kidney disease. Thus, plenty of studies have attempted to discover naturally derived compounds displaying anti-obesity effects. In this study, we evaluated the inhibitory effects of morolic acid 3-O-caffeate (MAOC), extracted from Betula schmidtii, on adipogenesis. Treatment of 3T3-L1 cells with MAOC during adipogenesis significantly reduced lipid accumulation and decreased the expression of adiponectin, a marker of mature adipocytes. Moreover, the treatment with MAOC only during the early phase (day 0-2) sufficiently inhibited adipogenesis, comparable with the inhibitory effects observed following MAOC treatment during the whole processes of adipogenesis. In the early phase of adipogenesis, the expression level of Wnt6, which inhibits adipogenesis, increased by MAOC treatment in 3T3-L1 cells. To identify the gene regulatory mechanism, we assessed alterations in histone modifications upon MAOC treatment. Both global and local levels on the Wnt6 promoter region of histone H3 lysine 4 trimethylation, an active transcriptional histone marker, increased markedly by MAOC treatment in 3T3-L1 cells. Our findings identified an epigenetic event associated with inhibition of adipocyte generation by MAOC, suggesting its potential as an efficient therapeutic compound to cure obesity and metabolic diseases.

  View details for DOI 10.3390/molecules25245910

  View details for Web of Science ID 000603240400001

  View details for PubMedID 33322233

  View details for PubMedCentralID PMC7764869

• Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus VIRUSES-BASEL Yi, S., Nam, K., Yun, J., Gim, D., Joe, D., Kim, Y., Kim, H., Han, J., Lee, J. 2020; 12 (9)

  Abstract

  Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.

  View details for DOI 10.3390/v12091004

  View details for Web of Science ID 000581273300001

  View details for PubMedID 32911874

  View details for PubMedCentralID PMC7551632