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 late-stage patients, which is partly attributed to the major knowledge gap regarding liver cell heterogeneity and cell-specific 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 49 919 nuclei 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 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.

Membrane fusion-mediated delivery of small-molecule HER2 tyrosine kinase inhibitor for effective tumor chemosensitization.

Although nanocarriers have been widely applied in the delivery of anticancer drugs, many commercialized anticancer nanodrug systems still suffer from the problem of being easily trapped by lysosomes, which severely limits the drug delivery efficiency of a nanodrug system. Meanwhile, in drug-resistant tumors, the efflux of anticancer therapeutic drugs via the drug efflux transporters on the plasma membrane of cancer cells can significantly decrease the intracellular drug concentration and lead to the failure of the drug treatment. Here, we developed a small-molecule tyrosine kinase inhibitor (TKI)- and doxorubicin (Dox, a common anticancer drug)-loaded membrane fusion liposome (MFL) (termed Dox@Lapa-MFL) to achieve tumor cell membrane fusion-mediated drug delivery and enhanced chemotherapy of drug-resistant tumor. MFL could deliver drugs in a membrane fusion manner, circumventing the capture by lysosomes. Lapatinib, as the TKI doped in the MFL, could inhibit the efflux of Dox by ATP-binding cassette transporters (ABC transporters), further promoting the intracellular Dox accumulation. As a result, Dox achieved effective killing of drug-resistant tumors under the dual effect of MFL and lapatinib. To the best of our knowledge, it is the first example that employs membrane fusion-mediated TKI delivery for achieving tumor chemosensitization with good biosafety. This work presents an efficient and easily achievable strategy for treating drug-resistant tumors, which may hold promise for clinical applications.

The Chromosome-Based Rubber Tree Genome Provides New Insights into Spurge Genome Evolution and Rubber Biosynthesis.

The rubber tree, Hevea brasiliensis, produces natural rubber that serves as an essential industrial raw material. Here, we present a high-quality reference genome for a rubber tree cultivar GT1 using single-molecule real-time sequencing (SMRT) and Hi-C technologies to anchor the ∼1.47-Gb genome assembly into 18 pseudochromosomes. The chromosome-based genome analysis enabled us to establish a model of spurge chromosome evolution, since the common paleopolyploid event occurred before the split of Hevea and Manihot. We show recent and rapid bursts of the three Hevea-specific LTR-retrotransposon families during the last 10 million years, leading to the massive expansion by ∼65.88% (∼970 Mbp) of the whole rubber tree genome since the divergence from Manihot. We identify large-scale expansion of genes associated with whole rubber biosynthesis processes, such as basal metabolic processes, ethylene biosynthesis, and the activation of polysaccharide and glycoprotein lectin, which are important properties for latex production. A map of genomic variation between the cultivated and wild rubber trees was obtained, which contains ∼15.7 million high-quality single-nucleotide polymorphisms. We identified hundreds of candidate domestication genes with drastically lowered genomic diversity in the cultivated but not wild rubber trees despite a relatively short domestication history of rubber tree, some of which are involved in rubber biosynthesis. This genome assembly represents key resources for future rubber tree research and breeding, providing novel targets for improving plant biotic and abiotic tolerance and rubber production.