Cell atlas of CCl_(4)-induced progressive liver fibrosis reveals stage-specific responses

Chronic liver injury leads to progressive liver fibrosis and ultimately cirrhosis,a major cause of morbidity and mortality worldwide.However,there are currently no effective anti-fibrotic therapies available,especially for latestage patients,which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cellspecific responses in different fibrosis stages.To reveal the multicellular networks regulating mammalian liver fibrosis from mild to severe phenotypes,we generated a single-nucleus transcriptomic atlas encompassing 49919nuclei corresponding to all main liver cell types at different stages of murine carbon tetrachloride(CCl_(4))-induced progressive liver fibrosis.Integrative analysis distinguished the sequential responses to injury of hepatocytes,hepatic stellate cells and endothelial cells.Moreover,we reconstructed the cell-cell interactions and gene regulatory networks implicated in these processes.These integrative analyses uncovered previously overlooked aspects of hepatocyte proliferation exhaustion and disrupted pericentral metabolic functions,dysfunction for clearance by apoptosis of activated hepatic stellate cells,accumulation of pro-fibrotic signals,and the switch from an anti-angiogenic to a pro-angiogenic program during CCl_(4)-induced progressive liver fibrosis.Our dataset thus constitutes a useful resource for understanding the molecular basis of progressive liver fibrosis using a relevant animal model.

Zoological Research Call for Papers:Special Issue on Single-Cell and Spatial-Omics

Single-cell and spatial-omic technologies are providing unprecedented detail into the molecular principles underlying a wide range of developmental and disease contexts.These observations are substantially deepening many areas of biological research.However,despite the increasing application of these techniques to biological problems we are only revealing the tip of the iceberg,and there exist large gaps in our understanding of the behavior of single cells in vitro and in vivo that need to be filled.Additionally,the development of robust analytical tools and meta-analysis of existing data lag behind the rapid generation of new data.

Towards a primate single-cell atlas

Biology in the 21st century is shifting substantially towards single-cell analysis.Mammalian tissues are highly heterogeneous and contain multiple cell types in different states whose tight coordination determines overall function.Bulk measurements,including RNA sequencing,provide average values,which may dilute cell-specific effects or overlook rare effects of functional importance.This greatly limits our understanding of mammalian physiology and disease.For example,the histological structures of the cortical and medullary regions of the kidney differ substantially,and their cells exhibit distinct characteristics related to environmental gradients such as oxygenation,glomerular filtrate-induced shear stress,and solute concentrations within the nephron.Furthermore,not all nephrons,mesenchymal cells,or vascular cells function in the same way,especially in the context of disease and aging.

Role of Long Non-coding RNAs in Reprogramming to Induced Pluripotency

The generation of induced pluripotent stem cells through somatic cell reprogramming requires a global reorganization of cellular functions.This reorganization occurs in a multi-phased manner and involves a gradual revision of both the epigenome and transcriptome.Recent studies have shown that the large-scale transcriptional changes observed during reprogramming also apply to long noncoding RNAs(lncR NAs),a type of traditionally neglected RNA species that are increasingly viewed as critical regulators of cellular function.Deeper understanding of lncR NAs in reprogramming may not only help to improve this process but also have implications for studying cell plasticity in other contexts,such as development,aging,and cancer.In this review,we summarize the current progress made in profiling and analyzing the role of lncR NAs in various phases of somatic cell reprogramming,with emphasis on the re-establishment of the pluripotency gene network and X chromosome reactivation.

Global Profiling of the Lysine Crotonylome in Different Pluripotent States

Pluripotent stem cells(PSCs)can be expanded in vitro in different culture conditions,resulting in a spectrum of cell states with distinct properties.Understanding how PSCs transition from one state to another,ultimately leading to lineage-specific differentiation,is important for developmental biology and regenerative medicine.Although there is significant information regarding gene expression changes controlling these transitions,less is known about post-translational modifications of proteins.Protein crotonylation is a newly discovered post-translational modification where lysine residues are modified with a crotonyl group.Here,we employed affinity purification of crotonylated(LC–MS/MS)to systematically profile protein crotonylation in mouse PSCs in different states including ground,metastable,and primed states,as well as metastable PSCs undergoing early pluripotency exit.We successfully identified 3628 high-confidence crotonylated sites in 1426 proteins.These crotonylated proteins are enriched for factors involved in functions/processes related to pluripotency such as RNA biogenesis,central carbon metabolism,and proteasome function.Moreover,we found that increasing the cellular levels of crotonyl-coenzyme A(crotonyl-CoA)through crotonic acid treatment promotes proteasome activity in metastable PSCs and delays their differentiation,consistent with previous observations showing that enhanced proteasome activity helps to sustain pluripotency.Our atlas of protein crotonylation will be valuable for further studies of pluripotency regulation and may also provide insights into the role of metabolism in other cell fate transitions.

Back to pluripotency:fully chemically induced reboot of human somatic cells

In a recent study published in Nature,Guan et al.1 showed an exciting strategy to reprogram human somatic cells into human chemically induced pluripotent stem cells(hCiPSCs).Thereby,they identified crucial steps and pathways that pose a barrier to chemically induced reprogramming of human cells.