Biology subjects

Seok, S. H.

Publications and source records attributed to Seok, S. H..

5 recordsLinked to original sources

bioRxiv2026

A macrophage-derived noncanonical WNT niche drives immune exclusion in pancreatic cancer

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterized by profound immune exclusion and resistance to immunotherapy. Although WNT signaling has been implicated in PDAC, its cellular source within the tumor microenvironment and its contribution to immune suppression remain poorly defined. This study investigated whether myeloid-derived WNT signaling promotes PDAC progression. MethodsTranscriptomic data from human PDAC cohorts, including The Cancer Genome Atlas (TCGA), and published single-cell RNA sequencing datasets were analyzed. Macrophage-associated WNT5A expression in human PDAC biopsies was assessed using in situ hybridization and immunofluorescence. Macrophage-derived WNT secretion was genetically disrupted using macrophage-specific Porcn knockout mice in orthotopic and subcutaneous KPC tumor models. Lineage-resolved spatial organization of macrophage subsets was characterized using Ms4a3 fate-mapping double-reporter mice with immunofluorescence and imaging mass cytometry. Macrophages-CD8 T cells interactions were assessed using tumor-educated macrophage conditioned media, pharmacologic ARG1 inhibition, and in vivo CD8 T cell depletion. ResultsPDAC tumors with high macrophage signatures showed enrichment of noncanonical WNT signaling, and macrophage-associated WNT5A was detected in human biopsies. Disruption of macrophage-derived WNT secretion suppressed tumor growth, reversed immune exclusion, and enhanced cytotoxic CD8 T cell infiltration. Spatial lineage-resolved analysis demonstrated progressive accumulation of Hexb tissue-resident macrophages that dominated advanced lesions and formed a WNT-rich niche closely associated with Trem2Arg1 monocyte-derived macrophages. Mechanistically, macrophage-derived noncanonical WNT activated a JNK/c-Jun-ARG1 axis that inhibited CD8 T cell proliferation, an effect abolished by myeloid WNT loss. ConclusionsMyeloid-derived noncanonical WNT establishes a lineage-structured macrophage niche that enforces immune exclusion in PDAC. Targeting macrophage-restricted WNT signaling represents a promising strategy to reprogram the PDAC immune microenvironment.

cancer biology↗

bioRxiv2026

A computational framework for designing micron-scale crisscross DNA megastructures

Crisscross polymerization enables the assembly of hundreds of unique DNA origami slats into micron-sized structures with nanoscale precision. To design these megastructures, thousands of handle sequences from a fixed library must be assigned to individual slats to encode the desired binding architecture. This complexity presents two major challenges: handles must be selected to minimize parasitic interactions that compete with desired assembly, and the fabrication of hundreds of unique slats creates a substantial logistical burden. Here, we develop a unified framework that standardizes the design and fabrication of crisscross megastructures. We use an evolutionary algorithm to optimize handle assignment and minimize parasitic binding between slats, paired with a graph-based algorithm that expands the handle library. Together, these algorithms enable the assembly of large, multi-layered megastructures that otherwise would be produced at negligible yields. We have released this framework as #-CAD, an open-source graphical application that integrates these algorithms, streamlines laboratory workflows, and makes crisscross DNA origami more broadly accessible.

synthetic biology↗

bioRxiv2025

Blocking CCR2+ Monocyte Infiltration Enhances Neurological Recovery after Subarachnoid Hemorrhage

BACKGROUNDSubarachnoid hemorrhage (SAH) patients mortality rate has been decreasing, but improving survivors prognosis outcome, which impacts patients quality of life, is still limited. An Early Brain Injury (EBI), which is a period of first 72 hours after SAH, is critical phase when resident and infiltrating innate immune cells induce neuroinflammation, deciding the prognosis outcome. While the roles of microglia have been studied, little is known about the role of infiltrating immune cells, especially that of monocytes. We investigated how the absence of monocyte infiltration during EBI may affect SAH outcomes. METHODSUsing Middle cerebral artery (MCA) perforation method, we established Wild type (WT) and C-C Chemokine Receptor type 2 (CCR2) knockout transgenic mice (CCR2-/-) SAH model. Using flow cytometry, we determined differences in immune cell infiltration population. Also, through Cytometric bead array (CBA), we measured inflammatory cytokine level. We performed different behavioral experiments to assess neurological and behavioral recovery and prognosis of SAH. Furthermore, to confirm neuronal cell death severity, immunohistochemistry was performed. We also tested CCR2 antagonists in the early EBI period to see if it impacted WT mices neurological outcome. RESULTSSAH model showed increased infiltration of CD45hi immune cells, mainly Ly6C+ monocyte at 24 hours after SAH, which were nearly abolished in CCR2-/- SAH mice. Increased IL-6 and TNF- cytokine levels in cerebrospinal fluid was significantly reduced as well. Also, better neurological and motor recovery was observed from CCR2-/- SAH mice. Overall neuronal cell death by late EBI period was significantly decreased. Finally, WT SAH mice treated with CCR2 antagonists showed improved neurological outcomes 24 hours after SAH, while showing reduced total infiltrating immune cells and monocytes. CONCLUSIONClassical monocyte infiltration, which occurs via CCR2 signaling, is detrimental for neuroinflammation during EBI of SAH that leads to poor prognosis. CCR2 inhibition could be a potential target for interventional therapeutic strategy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/644055v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@66726eorg.highwire.dtl.DTLVardef@1e2d390org.highwire.dtl.DTLVardef@afa86borg.highwire.dtl.DTLVardef@5a3f85_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

immunology↗

bioRxiv2021

Liposomal Dexamethasone Reduces A/H1N1 Influenza-Associated Morbidity in Mice

Re-emerging viral threats have continued to challenge the medical and public health systems. It has become clear that a significant number of severe viral infection cases are due to an overreaction of the immune system, which leads to hyperinflammation. In this study, we aimed to demonstrate the therapeutic efficacy of the dexamethasone nanomedicine in controlling the symptoms of influenza infection. We found that the A/Wisconsin/WSLH34939/2009 (H1N1) infection induced severe pneumonia in mice with a death rate of 80%, accompanied by significant epithelial cell damage, infiltration of immune cells, and accumulation of pro-inflammatory cytokines in the airway space. Moreover, the intranasal delivery of liposomal dexamethasone during disease progression reduced the death rate by 20%. It also significantly reduced the protein level of tumor necrosis factor-alpha (TNF), interleukin1{beta} (IL-1{beta}), IL-6, and the C-X-C motif chemokine ligand 2 (CXCL2) as well as the number of infiltrated immune cells in the bronchoalveolar lavage fluids as compared to the free drug. It was found that the liposomal dexamethasone was mainly distributed into the monocyte/macrophages in the lungs, suggesting its mode of action via the specific delivery of the drug into myeloid cells as a major cell population for inducing the cytokine storm. Taken together, the intranasal delivery of liposomal dexamethasone may serve as a novel promising therapeutic strategy for the treatment of influenza A-induced pneumonia. ImportanceInfluenza A virus causes annual epidemics and sporadic pandemics of respiratory diseases. An excessive immune response, called a cytokine storm, caused by the influenza virus is the most common complication of influenza infection that is associated with high levels of morbidity and mortality. Here, we report that the liposomal dexamethasone targeting the monocytes/macrophages during disease progression reduced the death rate as well as the protein level of inflammatory cytokines and the number of immune cells. Therefore, the findings of this study may be applied to address the limitations of the current strategies for the treatment of influenza.

immunology↗

bioRxiv2020

E prostanoid receptor 4 expressing macrophages promote the regeneration of the intestinal epithelial barrier upon inflammation

Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of resolution of inflammation but the mechanisms underlying their mucosal healing capacity remains elusive. Here, we describe a subset of E prostanoid receptor 4 (EP4) expressing intestinal macrophages with mucosal healing properties both in human and mice. Notably, Csf1r-iCre EP4-fl/fl mice showed defective mucosal healing and intestinal epithelial barrier regeneration in a dextran sodium sulfate-induced colitis model. Mechanistically, an increased mucosal level of prostaglandin E2 (PGE2) triggers the secretion of chemokine (C-X-C motif) ligand 1 (CXCL1) in monocyte-derived EP4+ macrophages via MAPKs. Subsequently, CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during the resolution phase of colitis. Thus, EP4+ intestinal macrophages are essential for the support of the intestinal stem cell niche and for the regeneration of the injured epithelium. One Sentence SummaryProstaglandin E2 licenses E-type prostanoid receptor 4 intestinal macrophage regenerative capacity promoting mucosal healing via the secretion of CXCL1

immunology↗