Biology subjects

Chung, L.

Publications and source records attributed to Chung, L..

7 recordsLinked to original sources

bioRxiv2026

Lymphatic CD49a is a driver of meningeal immune aging and cognitive decline.

Aging is associated with progressive accumulation and dysregulation of dural immune cells, coinciding with impaired CSF drainage and lymphatic function. Prior work has shown that improving lymphatic function in aged mice is sufficient to ameliorate age-associated cognitive decline, and that local immune cells can directly regulate lymphatic draining function. Yet, the endothelial-intrinsic mechanisms driving lymphatic dysfunction remain unclear. Here we found that the integrin CD49a is upregulated in aged lymphatic endothelial cells and regulates CCL21 release. Accordingly, genetic deletion of CD49a in lymphatic endothelial cells broadly reverses age-associated immune dysfunction across dural myeloid, lymphoid and dendritic cell compartments, limits glial aging, and mitigates cognitive and social behavioral deficits, thereby revealing a targetable endothelial-intrinsic mechanism of lymphatic aging.

neuroscience↗

bioRxiv2026

FMR1 reduction alters cellular and circuit properties in human cortex

Transcriptional silencing of FMR1 results in Fragile X syndrome (FXS), the leading inherited cause of intellectual disability (ID) and autism. The Fmr1-/y mouse model has been used to identify FXS disease mechanisms, whereas mechanistic insights from human brain are lacking. By leveraging organotypic human cortical slices and viral tools to reduce FMR1 expression, we create a new model that captures cell type-specific transcriptomic changes similar to FXS patient cortex that are not seen in the Fmr1-/y mouse. Among these are ion channel subunit changes in deep layer pyramidal neurons, which are consistent with a robust hyperexcitability seen by whole-cell patch-clamp recordings, and increased synchronized activity revealed by 2-photon calcium imaging. Together, this work defines the impact of FMR1 reduction in human cortex and provides a new model for testing therapeutic interventions in FXS.

neuroscience↗

bioRxiv2024

An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis and regression. Propranolol is the mainstay of treatment for IH. It inhibits hemangioma vessel formation via a {beta}-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial specific transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss of SOX18 function confirmed R(+) propranolol mode of action on the MVP. Functional validation in preclinical IH models revealed that statins - targeting the MVP - are potent inhibitors of hemangioma vessel formation. We propose a novel SOX18-MVP-axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. Our findings reveal novel pleiotropic effects of beta-blockers and statins acting on the SOX18-MVP axis to disable an endothelial specific program in IH, which may impact other scenarios involving pathological vasculogenesis and angiogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/577829v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@f02b2corg.highwire.dtl.DTLVardef@1a2790forg.highwire.dtl.DTLVardef@1ba0318org.highwire.dtl.DTLVardef@1213522_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Helminth egg derivatives as pro-regenerative immunotherapies

The immune system is increasingly recognized as an important regulator of tissue repair. We developed a regenerative immunotherapy from the helminth Schistosoma mansoni soluble egg antigen (SEA) to stimulate production of interleukin (IL)-4 and other type 2-associated cytokines without negative infection-related sequelae. The regenerative SEA (rSEA) applied to a murine muscle injury induced accumulation of IL-4 expressing T helper cells, eosinophils, and regulatory T cells, and decreased expression of IL-17A in gamma delta ({gamma}{delta}) T cells, resulting in improved repair and decreased fibrosis. Encapsulation and controlled release of rSEA in a hydrogel further enhanced type 2 immunity and larger volumes of tissue repair. The broad regenerative capacity of rSEA was validated in articular joint and corneal injury models. These results introduce a new regenerative immunotherapy approach using natural helminth-derivatives. One-Sentence SummaryHelminth-derived soluble egg antigen regenerative immunotherapies promote tissue repair in multiple injury models.

bioengineering↗

bioRxiv2019

Upstream translation initiation expands the coding capacity of segmented negative-strand RNA viruses

Segmented negative-strand RNA viruses (sNSVs) include the influenza viruses, the bunyaviruses, and other major pathogens of humans, other animals and plants. The genomes of these viruses are extremely short. In response to this severe genetic constraint, sNSVs use a variety of strategies to maximise their coding potential. Because the eukaryotic hosts parasitized by sNSVs can regulate gene expression through low levels of translation initiation upstream of their canonical open reading frames (ORFs), we asked whether sNSVs could use upstream translation initiation to expand their own genetic repertoires. Consistent with this hypothesis, we showed that influenza A viruses (IAVs) and bunyaviruses were capable of upstream translation initiation. Using a combination of reporter assays and viral infections, we found that upstream translation in IAVs can initiate in two unusual ways: through non-AUG initiation in virally encoded untranslated regions, and through the appropriation of an AUG-containing leader sequence from host mRNAs through viral cap-snatching, a process we termed start-snatching. Finally, while upstream translation of cellular genes is mainly regulatory, for sNSVs it also has the potential to create novel viral gene products. If in frame with a viral ORF, this creates N-extensions of canonical viral proteins. If not, it allows the expression of cryptic overlapping ORFs, which we found were highly conserved in IAV and widely distributed in peribunyaviruses. Thus, by exploiting their hosts capacity for upstream translation initiation, sNSVs can expand still further the coding potential of their extremely compact RNA genomes.

molecular biology↗

bioRxiv2019

Single cell RNA-seq in regenerative and fibrotic biomaterial environments defines new macrophage subsets

Macrophages play diverse roles in the immune response to infection, cancer, and wound healing where they respond to local environmental signals, yet identification and phenotypic characterization of functional subsets in vivo remains limited. We performed single cell RNA sequencing analysis on differentiated macrophages sorted from a biologic matrix-induced regenerative environment versus a synthetic biomaterial foreign body response (FBR), characterized by TH2/interleukin (IL)-4 and TH17/IL-17, respectively. In the regenerative environment, unbiased clustering and pseudotime analysis revealed distinct macrophage subsets responsible for antigen presentation, chemoattraction, and phagocytosis, as well as a small population with expression profiles of both dendritic cells and skeletal muscle. In the FBR environment, we identified a CD9hi+IL-36{gamma}+ macrophage subset that expressed TH17-associated molecules characteristic of certain auto-immune responses that were virtually absent in mice lacking the IL-17 receptor. Surface marker combinations including CD9 and CD301b defined macrophage fibrotic and regenerative subsets enabling functional assessment and identification in human tissue. Application of the terminal macrophage subsets to train the SingleCellNet algorithm and comparison to human and mouse macrophages in tumor, lung, and liver suggest broad relevance of macrophage classification. These distinct macrophage subsets demonstrate previously unrecognized myeloid phenotypes involved in different tissue responses and provide new targets for potential therapeutic modulation of certain pathologic states and tissue repair.

immunology↗

bioRxiv2019

Interleukin 17 and senescence regulate the foreign body response

Synthetic biomaterials and medical devices suffer to varying levels from fibrosis via the foreign body response (FBR). To explore mechanistic connections between the immune response and fibrosis from the FBR, we first analyzed fibrotic capsule surrounding human breast implants and found increased numbers of interleukin (IL)17-producing {gamma}{delta}+ T cells and CD4+ TH17 cells as well as senescent cells. Further analysis in a murine model demonstrated an early innate IL17 response to synthetic implants, mediated by innate lymphoid cells and {gamma}{delta}+ T cells, was followed by a chronic adaptive antigen dependent CD4+ TH17 cell response. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to materials and the development of p16INK4a senescent cells. Treatment with a senolytic agent reduced IL17 expression and fibrosis. Discovery of a feed-forward loop between the TH17 and senescence response to synthetic materials introduces new targets for therapeutic intervention in the foreign body response.

immunology↗