Biology subjects

Li, Y.-N.

Publications and source records attributed to Li, Y.-N..

9 recordsLinked to original sources

bioRxiv2026

Spatial proteomic profiling of cardiac stromal populations and microenvironments in systemic sclerosis-associated primary myocardial involvement

Objectives: To define cardiac stromal heterogeneity and spatial stromal-immune organization in systemic sclerosis-associated virus-negative myocarditis (SSc-VNM), a manifestation of primary SSc heart involvement. Methods: Imaging mass cytometry, a single-cell multiplexed spatial proteomic technology, was applied to endomyocardial biopsies from ten patients with SSc-VNM, seven with VNM associated with other systemic autoimmune rheumatic diseases (a-VNM) and nine with isolated VNM (i-VNM). Single-cell phenotyping, cellular-neighborhood and spatial-interaction analyses, and correlations with histological fibrosis were performed at patient level. Results: Among 82,673 segmented cells, we identified seven fibroblast phenotypes and one CD34+ stromal-cell population. The overall fibroblast/stromal compartment was expanded in SSc-VNM compared with i-VNM (adjusted p = 0.00973). The composition of fibroblasts/stromal cells differed profoundly in SSc-VNM compared with a-VNM and i-VNM, with numerical increases in CD34+ stromal cells and SOX9+ and PI16high/POSTNhigh fibroblasts and de-enrichment of FAPhigh/POSTNhigh fibroblasts and myofibroblasts. Spatial analysis identified ten cellular neighborhoods and revealed distinct SSc-VNM-associated patterns, including altered stromal-immune interaction networks. These included enriched interactions of CD34+ stromal cells and PI16high/POSTNhigh fibroblasts with CD163high/HLA-DR+ macrophages and CD68+ mast cells. PI16high/POSTNhigh and PI16-/POSTNhigh fibroblasts demonstrated the highest collagen type 1 expression among all stromal cell subsets across all VNM entities and PI16high/POSTNhigh fibroblasts were numerically increased in biopsies with [≥]10% fibrotic remodeling and were spatially associated with collagen-rich areas. Conclusions: Our findings refine current concepts of human fibrotic myocardial remodeling and support therapeutic targeting of specific stromal players such as POSTNhigh fibroblast subpopulations. Keywords: Systemic Sclerosis; Myocarditis; Myocardial Fibrosis; Fibroblasts; Imaging Mass Cytometry.

bioinformatics↗

bioRxiv2026

Spatial organization of fibroblast subpopulations and niches across acute repair and chronic fibrotic remodeling of the human myocardium

Myocardial fibrosis is a common end point of acute and chronic cardiovascular injury, yet the spatially organized fibroblast (Fb) and immune-cell states that sustain fibrotic remodeling across etiologies remain incompletely defined. We applied cyclic in situ hybridization (cISH)-based spatial transcriptomics to myocardial biopsies from patients with acute myocardial infarction (AMI), ischemic cardiomyopathy (ICM), hypertrophic cardiomyopathy (HCM), postviral myocardial fibrosis (PVMF), and systemic sclerosis associated primary heart involvement (SSc-pHI). CODEX-based protein imaging provided orthogonal support for cell subpopulations and cellular neighborhoods. Spatially informed clustering identified six Fb subpopulations: COL1A1hi/POSTNhi, NOTCH3+, TIMP1hi, GSNhi/DCNhi, AP1hi Fbs, and myofibroblasts. COL1A1hi/POSTNhi and NOTCH3+ Fbs were enriched in AMI, whereas GSNhi/DCNhi Fbs and myofibroblasts predominated in chronic fibrotic remodeling. These subpopulations displayed distinct extracellular matrix, inflammatory, and vasoregulatory programs. Infarction-associated reparative niches were enriched in COL1A1hi/POSTNhi or NOTCH3+ Fbs and SPP1+ or APOE+ macrophages (M{Phi}), whereas chronic fibroinflammatory niches were enriched in GSNhi/DCNhi or AP1hi Fbs or myofibroblasts with C1Q+ M{Phi} and plasma cells. The GSNhi/DCNhi Fb niche marked areas of subendocardial fibrosis, whereas the AP1hi Fb niche localized to perivascular fibrosis. In SSc-pHI, the actively fibrogenic COL1A1hi/POSTNhi Fb state characteristic of infarct scar formation was present at higher frequency than in other chronic entities and was individually associated with cardiac dysfunction, whereas the chronic GSNhi/DCNhi Fb niche was associated with the extent of interstitial fibrosis and anti-topoisomerase I autoantibodies. These data show that human myocardial fibrosis is organized into spatially distinct Fb subpopulations that assemble into context-specific fibroinflammatory niches across chronic fibrotic remodeling and repair after AMI.

cell biology↗

bioRxiv2025

Excitatory neurons as the default fate in bifurcation of excitatory and inhibitory neuron lineages

In the brain, a precise excitation-inhibition balance underpins every neural operation. Strikingly, across the vertebrate CNS, excitatory and inhibitory neurons often emerge from common progenitors (termed EX-IN lineage), yet how such dichotomous fates diverge has remained enigmatic. Here, exploiting spinal v2a (excitatory)-v2b (inhibitory) and retinal bipolar (excitatory) - amacrine (inhibitory) lineages as EX-IN lineage paradigm, we report a single, conserved genetic program: excitatory neural fate is the default state when sibling-cell communication is silenced; progenitor- and excitatory neuron-expressed homeobox genes actively repress the inhibitory program, while Notch signaling releases this repression to unleash inhibitory identity. Thus, we define a unifying principle governing EX-IN lineage divergence that generate the fundamental dichotomy of neural circuits.

developmental biology↗

bioRxiv2025

Distinct myeloid precursors and their interaction with mesenchymal cells orchestrate the spreading of psoriatic disease from the skin to the joints

Psoriatic disease initially affects the skin, but later extends to the joints. Herein, we describe a two-step process that orchestrates spreading of inflammation from the skin to the joints. Induction of psoriatic skin disease in photoconvertible mice, followed by sequencing and computational characterization of skin-derived cells in the joints, identified a unique population of CD2+ MHC-II+ CCR2+ myeloid precursors that built up a skin-derived myeloid cell compartment in the joints. Single-cell cross-species reference mapping and mitochondrial variant tracing showed an orthologue human cell population. Interactome analyses in the joints showed that in a second step, resident regulatory CD200+ fibroblasts critically regulate the priming of the CD2+ MHC-II+ CCR2+ myeloid precursors, which subsequently regulate the IL-17 expression in T cells. Hence, spreading of inflammation requires a distinct migratory myeloid precursor population and a permissive local tissue environment, similar to tumour metastasis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/665302v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@38c440org.highwire.dtl.DTLVardef@dc574dorg.highwire.dtl.DTLVardef@1e79f72org.highwire.dtl.DTLVardef@19508cf_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Single cell mapping of the metabolic landscape of skin fibrosis in systemic sclerosis

AbstractTissue resident cells undergo metabolic reprogramming during fibrotic tissue remodeling to meet their changing metabolic demands required for extracellular matrix production and phenotypic transitions in fibrosis. However, the metabolic reprogramming in fibrotic tissues has not yet been explored at single cell level with spatial resolution. Moreover, the spatial organization of metabolic niches in fibrotic tissues remains understudied. To address these gaps, we used imaging mass cytometry (IMC) and characterized the metabolic regulome, indicative of the activity in several key metabolic pathways in systemic sclerosis (SSc) as a prototypic systemic fibrotic disease. We identified a distinct metabolically active profile with high activity of glycolysis, TCA/OXPHOS, hypoxia and ROS signaling in fibroblasts, endothelial cells and macrophages in SSc patients with progressive skin fibrosis. These metabolic profiles are associated with expression of markers of profibrotic activation. Metabolically active fibroblasts might shape their microenvironment to induce a similar metabolic phenotype in neighboring endothelial cells and macrophages, facilitating profibrotic interactions. Consistently, specific interactions between metabolically defined, activated cell subsets are associated with the extent or progression of skin fibrosis. Thus, interfering with these metabolic niches might provide therapeutic opportunities in fibrotic diseases.

cell biology↗

bioRxiv2025

Mapping spatially-resolved transcriptomes in systemic sclerosis

Systemic sclerosis (SSc) is a prototypical fibrotic disease with high mortality and limited treatment options. Despite advances in single-cell RNA sequencing (scRNA-seq), the comprehensive understanding of cellular heterogeneity and cell-cell interaction within the fibrogenesis microenvironment remains limited. We generated spatially resolved transcriptome maps from healthy and SSc skin and built a scRNA-seq atlas to map the single-cell data to spatial space. This enabled us to identify a fibrotic niche, enriched with fibroblasts and macrophages, which is significantly expanded in SSc and correlated with clinical outcome. We revealed disease-specific cell states of fibroblasts and macrophages, and evaluated their spatial dependency on other cell types. We identified selective expression of ACKR3 in fibroblast progenitors that diminishes with SSc progression, which may serve to regulate CXCL12/CXCR4-mediated macrophage recruitment and fibrotic remodeling. Together, we provided an in-depth description at cellular and spatial levels of fine-tuned regulatory events occurring in SSc, offering spatiotemporal insights. One Sentence SummaryIntegrated spatial omics provide insight into the cellular and transcriptional landscape in spatially distinct microenvironments, which may drive fibrosis progression in SSc.

immunology↗

bioRxiv2024

Spatially informed phenotyping by cyclic-in-situ-hybridization identifies novel fibroblast populations and their pathogenic niches in systemic sclerosis

Spatially non-resolved transcriptomic data identified functionally distinct populations of fibroblasts in health and disease. However, in-depth transcriptional profiling in situ at single-cell resolution has not been possible so far. Here, we studied fibroblast populations in the skin of SSc patients and healthy individuals using cyclic in situ hybridization (cISH) as a novel approach for spatially-resolved transcriptional phenotyping with subcellular resolution. cISH deconvoluted the heterogeneity of 20,979 cells including 3,764 fibroblasts (FB). BANKSY-based spatially-informed clustering identified nine FB subpopulations, with SFRP2+ RetD FB and CCL19+ nonPV FB as novel subpopulations that reside in specific cellular niches and display unique gene expression profiles. SFRP2+ RetD FB and CCL19+ nonPV FB as well as COL8A1+ FB, display altered frequencies in SSc skin and play specific, disease-promoting roles for extracellular matrix release and leukocyte recruitment as revealed by their transcriptional profile, their cellular interactions and ligand-receptor analyses. The frequencies of COL8A1+ FB and their interactions with monocytic cells and B cells are associated with progression of skin fibrosis in SSc. In summary, our spatially-resolved transcriptomic approach identified novel fibroblast subpopulations deregulated in SSc skin with specific pathogenic roles, some of which may potentially serve as biomarkers for progression of skin fibrosis.

immunology↗

bioRxiv2021

ACKR3 induces the perturbation of rRNA biogenesis: a novel mechanism of colorectal tumorigenesis

Atypical chemokine receptor 3 (ACKR3), previously known as C-X-C chemokine receptor type 7 (CXCR7), has emerged as a key player in several biologic processes. Its atypical "intercepting receptor" signaling properties have established ACKR3 as the main regulator in pathophysiological processes in many diseases. However, much less is known the underlying mechanisms of ACKR3 in promoting tumorigenesis. We found, in both human and animal model, that activation of ACKR3 promotes colorectal tumorigenesis through the NOLC1-induced perturbations of rRNA biogenesis. As compared with adjacent non-neoplastic tissue, human colonic cancer tissues demonstrated higher expression of ACKR3, and high ACKR3 expression was associated with increased severity of colonic cancer. Villin-ACKR3 transgenic mice demonstrated the characteristics of ACKR3-induced colorectal cancer, showing the nuclear {beta}-arrestin-1-activated perturbation of rRNA biogenesis. Activation of ACKR3 induced nuclear translocation of {beta}-arrestin-1 ({beta}-arr1), leading to the interaction of {beta}-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). As the highly phosphorylated protein in the nucleolus, NOLC1 further interacted with Fibrillarin, a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation, leading to the increase of methylation in Histone H2A, resulting in the promotion of rRNA transcription of ribosome biogenesis. Conclusion: ACKR3 promotes colorectal tumorigenesis through the perturbation of rRNA biogenesis by nuclear {beta}-arr1-induced interaction of NOLC1 with Fibrillarin. HIGH LIGHTSO_LIACKR3 is an atypical G protein-coupled receptor (GPCR) C_LIO_LIACKR3 promotes colorectal tumorigenesis C_LIO_LIACKR3 induces nuclear translocation of {beta}-arr1 C_LIO_LINuclear {beta}-arr1 interacts with NOLC1 to activate Fibrillarin C_LIO_LIInteraction of NOLC1 to Fibrillarin leads to perturbation of rRNA biogenesis C_LI

cancer biology↗

bioRxiv2019

Defective photosynthetic adaptation mechanism in winter restricts the introduction of overwintering plant to high latitudes

Because of the need for agriculture and landscaping, many overwintering evergreen and biennial species that maintain green leaves over winter were introduced to higher latitudes. The green leaves of introduced overwintering species have to withstand a harsher winter, especially lower temperature, than in their native region of origin. Although the responses and adaptability of photosynthetic apparatus to winter conditions in native overwintering species were widely studied, the experimental results on the introduced overwintering species are very limited. Here, the photosynthetic adaptability during winter was analyzed in two native overwintering species, pine (woody plants), winter wheat (herb), and two introduced overwintering species, bamboo (woody plants), lilyturf (herb). The native species exhibited higher capacity for photosynthetic CO2 fixation and lower susceptibility for photoinhibition than introduced species during winter. Photosynthesis related proteins, such as PsbA, PsaA, Rubisco and Lhcb1, were marginally affected in native species, but significantly degraded in introduced species during winter. More interestingly, the PSII photoinhibition was mainly caused by up-regulation of photoprotection mechanism, non-photochemical quenching, in native species, but by photodamage in introduced species. This study indicates that the growth and survival of introduced overwintering species is limited by their photosynthetic adaptability to the harsher winter conditions at high latitudes.

plant biology↗