Biology subjects

Tung, L. W.

Publications and source records attributed to Tung, L. W..

4 recordsLinked to original sources

bioRxiv2026

Homeostatic fibroblast niche collapse in clinically uninvolved skin marks a pre-fibrotic stage of systemic sclerosis

Systemic sclerosis, or scleroderma, is a chronic autoimmune disease characterized by vasculopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. Heterogeneous clinical presentation and polygenic risk complicate our understanding of disease mechanisms and the path to effective therapy. Single-cell analyses have revealed substantial transcriptional diversity in skin, but disease-associated reprogramming remains poorly defined. To address this, we performed high-resolution spatial transcriptomic profiling of paired clinically uninvolved and clinically affected scleroderma donor skin alongside healthy controls. We identified a continuum of cellular, molecular, and spatial changes to the stroma that were already evident in clinically uninvolved tissue yet still distinct from the broader and more advanced changes in paired fibrotic samples. Uninvolved skin was comparable to healthy tissue by clinical and histopathological assessment, but distinguishable by the numerical reduction, transcriptional reprogramming, and spatial isolation of LGR5+SCARA5+PI16+ progenitor fibroblasts. In parallel, the dermal vascular smooth muscle compartment shifted from a contractile to a synthetic, activated state, suggesting reprogramming that begins before overt fibrosis. Cell neighborhood analysis revealed that progenitor fibroblasts occupy dense stromal niches in healthy skin that collapse in clinically uninvolved tissue, replaced by isolated, disease-associated cellular networks. These data indicate that clinically uninvolved skin occupies an intermediate stage along the pathologic continuum of scleroderma, establishing a framework for strategies to preserve homeostatic fibroblast niches before tissue remodeling and fibrotic commitment.

immunology↗

bioRxiv2026

UC-associated autoantibodies to αvβ6 inhibit mucosal TGFβ activation and predispose to intestinal inflammation

Ulcerative colitis (UC) is characterized by epithelial barrier dysfunction and dysregulated mucosal immune responses; however, the mechanisms driving disease onset remain poorly defined. Autoantibodies against the epithelial-restricted integrin v{beta}6 are a highly specific biomarker of UC that can precede clinical diagnosis by up to 10 years. Because v{beta}6 activates TGF{beta} at epithelial surfaces, we hypothesized that UC-associated v{beta}6 autoantibodies inhibit mucosal TGF{beta} activation and disrupt epithelial homeostasis. We showed that v{beta}6 autoantibodies were enriched in UC and that IgG from autoantibody-positive individuals inhibited v{beta}6-dependent activation of TGF{beta}. v{beta}6 blockade dampened TGF{beta} signaling and altered differentiation-associated gene programs in human intestinal epithelial cells. In mice, deletion of v caused expansion of inflammation-associated goblet cells in the colon and changes in intestinal immune cells. Using a novel mouse model, we showed that v{beta}6-specific autoantibody disrupted epithelial-immune crosstalk and increased susceptibility to DSS colitis. Together, these findings establish anti-v{beta}6 autoantibodies as active inhibitors of epithelial TGF{beta} signaling, constituting a de facto anti-cytokine response, rather than passive biomarkers. By linking preclinical seropositivity to impaired epithelial signaling and heightened susceptibility to colitis, this work identifies epithelial v{beta}6-dependent TGF{beta} activation as a pathway that may be leveraged to modify disease risk or limit disease severity. One Sentence SummaryUC-associated autoantibodies impair epithelial TGF{beta} activation, alter mucosal homeostasis, and predispose to colitis.

immunology↗

bioRxiv2022

Spatial compartmentalization of signalling imparts source-specific functions on secreted factors

Efficient regeneration requires multiple cell types acting in a coordination. To better understand the intercellular networks involved and how they change when regeneration fails, we profiled the transcriptome of hematopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. A time-resolved computational model of interactions was generated, and VEGFA-driven endothelial engagement was identified as a key differentiating feature in models of successful and failed regeneration. In addition, it revealed that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we deleted VEGFA from two cell types residing in close proximity, stromal and myogenic progenitors. By comparing responses to different types of damage, we found that myogenic and stromal VEGFA have distinct functions in regeneration. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communication networks. HighlightsO_LILigand-receptor signaling redundancy during skeletal muscle regeneration C_LIO_LIInflammatory cells, and muscle and fibro/adipogenic progenitors produce VEGFA C_LIO_LIVEGFA from muscle progenitors control their proliferation after muscle damage C_LIO_LIVEGFA from FAP controls angiogenesis only after ischemic damage C_LI eTOC blurbGroppa et al. performed a novel time-resolved bioinformatics analysis that revealed extensive ligand-receptor redundancy among the cell types contributing to skeletal muscle regeneration. They focused on one of these pathways, and showed that VEGFA from different cell types has distinct roles in regeneration.

cell biology↗

bioRxiv2021

Targeting fibrosis in the Duchenne Muscular Dystrophy mice model: an uphill battle

AimFibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects is available. Our goal is to unveil specific signallings regulating the fibrogenic process and to identify potential small molecule candidates that block fibrogenic differentiation of fibro/adipogenic progenitors. MethodWe performed a large-scale drug screen using muscle-resident fibro/adipogenic progenitors from a mouse model expressing EGFP under the Collagen1a1 promotor. We first confirmed that the EGFP was expressed in response to TGF{beta}1 stimulation in vitro. Then we treated cells with TGF{beta}1 alone or with drugs from two libraries of known compounds. The drugs ability to block the fibrogenic differentiation was quantified by imaging and flow cytometry. From a two-rounds screening, positive hits were tested in vivo in the mice model for the Duchenne muscular dystrophy (mdx mice). The histopathology of the muscles was assessed with picrosirius red (fibrosis) and laminin staining (myofiber size). Key findingsFrom the in vitro drug screening, we identified 21 drugs and tested 3 in vivo on the mdx mice. None of the three drugs significantly improved muscle histopathology. SignificanceThe in vitro drug screen identified various efficient compounds, none of them strongly inhibited fibrosis in skeletal muscle of mdx mice. To explain these observations, we hypothesize that in Duchenne Muscular Dystrophy, in which fibrosis is a secondary event due to chronic degeneration and inflammation, the drugs tested could have adverse effect on regeneration or inflammation, balancing off any positive effects and leading to the absence of significant results.

cell biology↗