Single-cell and spatially resolved transcriptomics for liver biology DOI
Ping Lin, Xi Yan, Siyu Jing

et al.

Hepatology, Journal Year: 2023, Volume and Issue: 80(3), P. 698 - 720

Published: April 1, 2023

Single-cell transcriptomics enables the identification of rare cell types and inference state transitions, whereas spatially resolved allows quantification cells genes in context tissues. The recent progress these new technologies is improving our understanding landscape its roles diseases. Here, we review key biological insights into liver homeostasis, development, regeneration, chronic disease, cancer obtained from single-cell transcriptomics. We highlight atlas that characterizes comprehensive cellular composition; diversity function; spatial architecture such as zonation, communication, proximity; identity conversion cell-specific alterations are associated with pathology; therapeutic targets. further discuss outstanding challenges, advanced experimental technologies, computational methods help to address challenges.

Language: Английский

Liver zonation, revisited DOI Creative Commons
J Paris, Neil C. Henderson

Hepatology, Journal Year: 2022, Volume and Issue: 76(4), P. 1219 - 1230

Published: Feb. 17, 2022

Abstract The concept of hepatocyte functional zonation is well established, with differences in metabolism and xenobiotic processing determined by multiple factors including oxygen nutrient levels across the hepatic lobule. However, recent advances single‐cell genomics technologies, nuclei RNA sequencing, rapidly evolving fields spatial transcriptomic proteomic profiling have greatly increased our understanding liver zonation. Here we discuss how these transformative experimental strategies are being leveraged to dissect at unprecedented resolution this new information should facilitate emergence novel precision medicine‐based therapies for patients disease.

Language: Английский

Citations

92
Biofabrication methods for reconstructing extracellular matrix mimetics DOI Creative Commons
Abdellah Aazmi, Duo Zhang,

Corrado Mazzaglia

et al.

Bioactive Materials, Journal Year: 2023, Volume and Issue: 31, P. 475 - 496

Published: Sept. 9, 2023

In the human body, almost all cells interact with extracellular matrices (ECMs), which have tissue and organ-specific compositions architectures. These ECMs not only function as cellular scaffolds, providing structural support, but also play a crucial role in dynamically regulating various functions. This comprehensive review delves into examination of biofabrication strategies used to develop bioactive materials that accurately mimic one or more biophysical biochemical properties ECMs. We discuss potential integration these ECM-mimics range physiological pathological vitro models, enhancing our understanding behavior organization. Lastly, we propose future research directions for context engineering organ-on-a-chip applications, offering advancements therapeutic approaches improved patient outcomes.

Language: Английский

Citations

58
Mitochondrial heterogeneity and adaptations to cellular needs DOI
Melia Granath-Panelo, Shingo Kajimura

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(5), P. 674 - 686

Published: May 1, 2024

Language: Английский

Citations

18
Human-correlated genetic models identify precision therapy for liver cancer DOI Creative Commons
Miryam Müller, Stephanie May, H. G. HALL

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause cancer-related mortality worldwide 1,2 . HCC occurs typically from background chronic disease, caused by spectrum predisposing conditions. Tumour development driven expansion clones that accumulate progressive driver mutations 3 , with hepatocytes likely cell origin 2 However, landscape in broadly independent underlying aetiologies 4 Despite an increasing range systemic treatment options for advanced HCC, outcomes remain heterogeneous and poor. Emerging data suggest drug efficacies depend on disease aetiology genetic alterations 5,6 Exploring subtypes preclinical models human relevance will therefore be essential to advance precision medicine 7 Here we generated suite genetically immunocompetent vivo matched vitro models. Our represent multiple features including clonal origin, histopathological appearance metastasis. We integrated transcriptomic mouse identified four human–mouse subtype clusters. The clusters had distinct characteristics aligned histopathology. In proof-of-principle analysis, verified response standard-of-care used linked vitro–in pipeline identify promising therapeutic candidate, cladribine, has not previously been treatment. Cladribine acts highly effective subtype-specific manner combination therapy.

Language: Английский

Citations

2
Loss of liver function in chronic liver disease: An identity crisis DOI Creative Commons
Carmen Berasain, María Arechederra, Josepmaría Argemí

et al.

Journal of Hepatology, Journal Year: 2022, Volume and Issue: 78(2), P. 401 - 414

Published: Sept. 15, 2022

Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes proteins needed to perform complex metabolic secretory functions mature liver. Transient hepatocellular dedifferentiation can occur as part regenerative mechanisms triggered in response acute liver injury. However, persistent downregulation key genes now accepted a strong determinant organ dysfunction chronic disease, major global health burden. Therefore, identification core factors regulators that preserve phenotype, thorough understanding how these networks become disrupted diseased hepatocytes, high clinical relevance. In this context, we review players differentiation discuss detail critical such HNF4α, whose impairment mediates breakdown function. Moreover, present compelling experimental evidence demonstrating restoration factor expression chronically injured reset identity, improve function ameliorate structural abnormalities. The possibility correcting phenotype severely damaged malfunctional livers may reveal new therapeutic opportunities for individuals cirrhosis advanced disease.

Language: Английский

Citations

56
Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation DOI Creative Commons
Shirong Wang, Lin Zha, Xin Cui

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(20)

Published: June 6, 2023

Abstract While extensive investigations have been devoted to the study of genetic pathways related fatty liver diseases, much less is known about epigenetic mechanisms underlying these disorders. DNA methylation an link between environmental factors (e.g., diets) and complex diseases non‐alcoholic disease). Here, it aimed role in regulation hepatic lipid metabolism. A dynamic change methylome high‐fat diet (HFD)‐fed mice discovered, including a marked increase at promoter Beta‐klotho ( Klb) , co‐receptor for biological functions fibroblast growth factor (FGF)15/19 FGF21. methyltransferases (DNMT) 1 3A mediate HFD‐induced Klb promoter. Notably, HFD enhances DNMT1 protein stability via ubiquitination‐mediated mechanism. Liver‐specific deletion Dnmt1 or 3a increases expression ameliorates steatosis. Single‐nucleus RNA sequencing analysis reveals involved acid oxidation ‐deficient hepatocytes. Targeted demethylation oxidation, resulting decreased accumulation. Up‐regulation by may induce hypermethylation subsequent down‐regulation expression, development

Language: Английский

Citations

31
Spatial metabolomics and its application in the liver DOI Creative Commons
André A. Santos,

Teresa C. Delgado,

Vanda Marques

et al.

Hepatology, Journal Year: 2023, Volume and Issue: 79(5), P. 1158 - 1179

Published: Feb. 22, 2023

Hepatocytes work in highly structured, repetitive hepatic lobules. Blood flow across the radial axis of lobule generates oxygen, nutrient, and hormone gradients, which result zoned spatial variability functional diversity. This large heterogeneity suggests that hepatocytes different zones may have distinct gene expression profiles, metabolic features, regenerative capacity, susceptibility to damage. Here, we describe principles liver zonation, introduce metabolomic approaches study liver, highlight possibility exploring profile, leading a deeper understanding tissue organization. Spatial metabolomics can also reveal intercellular its contribution disease. These facilitate global characterization function with high resolution along physiological pathological time scales. review summarizes state art for spatially resolved analysis challenges hinder achievement metabolome coverage at single-cell level. We discuss several major contributions metabolism conclude our opinion on future developments applications these exciting new technologies.

Language: Английский

Citations

28
A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes DOI Creative Commons
Shanshan Yang, Chengyu Liu, Mengmeng Jiang

et al.

Protein & Cell, Journal Year: 2023, Volume and Issue: 15(2), P. 98 - 120

Published: June 28, 2023

Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes underlying mechanism aging in higher vertebrates remain incompletely characterized. Here, we constructed first single-nucleus transcriptomic landscape primate aging, which resolved gene expression fluctuation hepatocytes across three zonations detected aberrant cell-cell interactions between niche cells. Upon in-depth dissection this rich dataset, identified impaired lipid metabolism upregulation chronic inflammation-related genes prominently associated with declined functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark aged liver, consequently, forced activation SREBP2 human primary recapitulated vivo phenotypes, manifesting as detoxification accelerated cellular senescence. This study expands our knowledge informs development diagnostics therapeutic interventions for

Language: Английский

Citations

28
Desorption electrospray ionization mass spectrometry imaging (DESI-MSI) in disease diagnosis: an overview DOI
Bharath Sampath Kumar

Analytical Methods, Journal Year: 2023, Volume and Issue: 15(31), P. 3768 - 3784

Published: Jan. 1, 2023

Illustration of critical keywords pertaining to ambient mass spectrometry imaging in disease diagnosis research.

Language: Английский

Citations

26
Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans DOI Creative Commons

Kodihalli C. Ravindra,

Vishal S. Vaidya, Zhenyu Wang

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 3, 2023

Abstract Diagnosis of drug-induced liver injury (DILI) and its distinction from other diseases are significant challenges in drug development clinical practice. Here, we identify, confirm, replicate the biomarker performance characteristics candidate proteins patients with DILI at onset (DO; n = 133) follow-up ( 120), acute non-DILI (NDO; 63) 42), healthy volunteers (HV; 104). Area under receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94–0.99) DO HV. In addition, show that FBP1, alone or combination glutathione S-transferase A1 leukocyte cell-derived chemotaxin 2, could potentially assist diagnosis by distinguishing NDO (AUC range: 0.65–0.78), but further technical validation these biomarkers is needed.

Language: Английский

Citations

23