Biology subjects

Kong, K.

Publications and source records attributed to Kong, K..

6 recordsLinked to original sources

bioRxiv2025

Human hepatic stellate cells orchestrate the accumulation and function of CD103+ tissue-resident CD8+ T-cells in liver fibrosis

Tissue-resident memory cells (TRM) contribute to protective and pathogenic responses in the liver, yet precisely how hepatic TRM adapt and integrate cues from the underlying stroma and extracellular matrix (ECM) in chronic liver disease (CLD) has yet to be fully defined. Here we describe a role for activated myofibroblast-like hepatic stellate cells (HSCs) in the accumulation and in situ localisation of CD8+ TRM in the CLD liver. Activated HSCs drive a program of tissue residence in activated, tissue-infiltrating CD8+ T-cells in a TGF{beta}-dependent manner. We show upregulation of CD103, ECM-binding integrins and adhesion molecules driven by TGF{beta} which together contribute to the sequestration of TRM within the ECM-rich fibrotic niche. Ex vivo, hepatic CD103+ TRM correlate with the extent of ECM deposited, express an altered repertoire of co-stimulatory and co-inhibitory receptors, transcriptional regulators of cellular exhaustion and produce less proinflammatory mediators upon TCR engagement in CLD than in health. Through expression of several co-inhibitory ligands, we further demonstrate the potential for activated HSCs to acquire an immunomodulatory phenotype and limit the capacity of CD103+ TRM to produce anti-viral and anti-tumour mediators upon antigen encounter. Finally, we demonstrate that strategies to block such regulatory pathways, including the PD1:PD-L1/PD-L2 axis, have the potential to restore the antigen-specific effector function of tissue-compartmentalised CD103+ TRM and thus contribute to improving the effectiveness of local immunosurveillance in CLD. One Sentence Summary: Activated hepatic stellate cells characteristic of liver fibrosis orchestrate an accumulation of a CD103+ TRM population with a reduced capacity for antigen-specific effector function in human CLD.

immunology↗

bioRxiv2025

Conserved lipid metabolic reprogramming confers hypoxic and aging resilience

The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unknown. Here, we use lipidomic and metabolomic profiling to discover specific downregulation of triglyceride lipids and upregulation of the lipid biosynthetic precursor malonic acid in AGS neural stem cells (NSC) versus murine NSCs. Inhibiting lipid biosynthesis recapitulates hypoxic resilience of squirrel NSCs. Extending this model, we find that acute exposure to hypoxia downregulates key lipid biosynthetic enzymes in C. elegans, while inhibiting lipid biosynthesis reduces mitochondrial fission and facilitates hypoxic survival. Moreover, inhibiting lipid biosynthesis protects against APOE4-induced pathologies and aging trajectories in C. elegans. These findings suggest triglyceride downregulation as a conserved metabolic resilience mechanism, offering insights into protective strategies for neural tissues under hypoxic or ischemic conditions, APOE4-induced pathologies and aging.

physiology↗

bioRxiv2025

A Human Single-cell Atlas Identifies OLR1+ Scar-associated Macrophages as a Therapeutic Target for Chronic Liver Disease

Chronic liver disease (CLD) is a major global healthcare problem. Irrespective of cause, chronic damage to the liver results in fibrosis, which is associated with adverse clinical outcomes. Immune cells, in particular monocyte-derived macrophages (MDMs), are key regulators of fibrosis and represent an attractive therapeutic target for CLD. However, it has remained unclear which specific subpopulation of MDMs drives pro-inflammatory and pro-fibrotic functions in human CLD and how they might be selectively modulated. Here, we generate an annotated human liver single cell atlas from 42 healthy and 35 CLD patients, identifying 125 transcriptionally distinct cellular states. Leveraging large patient and cell numbers, our atlas resolves rare liver cell states and distinguishes two types of disease-expanded scar-associated macrophages (SAMac), including a specific subpopulation with a pro-inflammatory pro-fibrotic phenotype. The scavenger receptor OLR1 was enriched in pro-inflammatory SAMacs and high hepatic OLR1 expression was associated with increased mortality in CLD patients. A corresponding monocyte-derived OLR1+ SAMac subpopulation expanded in a mouse model of CLD and exhibited a pro-inflammatory phenotype based on single-cell RNA-seq, single-cell ATAC-seq, and flow cytometry analyses. Primary human OLR1+ MDMs promoted fibrogenic signalling in multilineage liver spheroid cultures, whilst specific targeting of OLR1 reduced IL-1{beta} production by human macrophages and attenuated myofibroblast activation. Overall, our annotated human liver single-cell atlas provides a valuable reference to study disease-associated cell states in CLD. We utilise this resource to identify a distinct pro-inflammatory subpopulation of SAMacs and highlight OLR1 as a potential therapeutic target to specifically modulate SAMac function and attenuate liver fibrosis.

immunology↗

bioRxiv2024

CREEPING STEM1 Regulates Directional Auxin Transport for Lodging Resistance in Soybean

Soybean, a staple crop on a global scale, frequently encounters challenges due to lodging under high planting densities, which results in significant yield losses. Despite extensive research, the fundamental genetic mechanisms governing lodging resistance in soybeans remain elusive. In this study, we identify and characterize the Creeping Stem 1 (CS1) gene, which plays a crucial role in conferring lodging resistance in soybeans. The CS1 gene encodes a HEAT-repeat protein that modulates hypocotyl gravitropism by regulating amyloplast sedimentation. Functional analysis reveals that the loss of CS1 activity disrupts polar auxin transport, vascular bundle development, and the biosynthesis of cellulose and lignin, ultimately leading to premature lodging and aberrant root development. Conversely, increasing CS1 expression significantly enhances lodging resistance and improves yield under conditions of high planting density. Our findings shed light on the genetic mechanisms that underlie lodging resistance in soybeans and highlight the potential of CS1 as a valuable target for genetic engineering to improve crop lodging resistance and yield.

plant biology↗

bioRxiv2020

Attractive internuclear force drives the collective behavior of nuclear arrays in Drosophila embryos

The emerging collective behaviors during embryogenesis play an important role in precise and reproducible morphogenesis. An important question in the study of collective behavior is what rule underlies the emerging pattern. Here we use the Drosophila embryo as a test tube to study this question. We focus on the nuclear array without membrane separation on the embryo periphery from the nuclear cycle (NC) 11 to NC14. After live imaging with light sheet microscopy, we extract the nuclear trajectory, speed, and internuclear distance with an automatic nuclear tracing method. We find that the nuclear speed shows a period of standing waves along the anterior-posterior (AP) axis after each metaphase as the nuclei collectively migrate towards the embryo poles and partially move back. And the maximum nuclear speed dampens by 38% in the second half of the standing wave. Moreover, the nuclear density is 35% higher in the middle than the pole region of the embryo during the S phase of NC11-NC14. To find mechanical rules controlling the collective motion and packing patterns of the nuclear array, we use the deep neural network (DNN) to learn the force field from data. We find two potential strong nuclear-age-dependent force fields, i.e., the repulsive or attractive force field. Simulations with the particle-based model indicate that only if the net internuclear force is attractive and increases with distance, the pseudo-synchronous mitotic wave in a nuclear array with lower nuclear density in embryo poles can drive the collective motion with the damped standing wave of the nuclear speed, and the collective nuclear motion, in turn, maintains the non-uniform nuclear density.

developmental biology↗

bioRxiv2019

The dynamic transmission of positional information in stau- mutants during Drosophila embryogenesis

Intriguingly, the developmental patterning during Drosophila embryogenesis is highly accurate and robust despite its dynamic changes and constant fluctuations. It has been suggested that Staufen (Stau) is key in controlling the boundary variability of the gap protein Hunchback (Hb). However, its underlying mechanism is still elusive. Here, we have developed methods to quantify the dynamic 3D expression of segmentation genes in Drosophila embryos. With improved control of measurement errors, our results reveal that the posterior boundary of the Hb anterior domain (xHb) of stau- mutants shows comparable variability to that of the wild type (WT) and shifts posteriorly by nearly 12% of the embryo length (EL) to the WT position in the nuclear cycle (nc) 14. This observed large shift might contribute significantly to the apparent large variability of xHb in previous studies. Moreover, for stau- mutants, the upstream Bicoid (Bcd) gradients show equivalent gradient noise to that of the WT in nc12-nc14, and the downstream Even-skipped (Eve) and cephalic furrow (CF) show the same positional errors as the WT. Our results indicate that threshold-dependent activation and self-organized filtering are not mutually exclusive but could both be implemented in early Drosophila embryogenesis.

developmental biology↗