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Understanding the liver stem cells (LSCs) holds great promise for new insights into liver diseases and liver regeneration. However, the heterogenicity and plasticity of liver cells have made it controversial. Here, by employing single‐cell RNA‐sequencing technology, transcriptome features of Krt19+ bile duct lineage cells isolated from Krt19CreERT; Rosa26R‐GFP reporter mouse livers are examined. Distinct biliary epithelial cells which include adult LSCs, as well as their downstream hepatocytes and cholangiocytes are identified. Importantly, a novel cell surface LSCs marker, CD63, as well as CD56, which distinguished active and quiescent LSCs are discovered. Cell expansion and bi‐potential differentiation in culture demonstrate the stemness ability of CD63+ cells in vitro. Transplantation and lineage tracing of CD63+ cells confirm their contribution to liver cell mass in vivo upon injury. Moreover, CD63+CD56+ cells are proved to be activated LSCs with vigorous proliferation ability. Further studies confirm that CD63+CD56− quiescent LSCs express VEGFR2 and FGFR1, and they can be activated to proliferation and differentiation through combination of growth factors: VEGF‐A and bFGF. These findings define an authentic adult liver stem cells compartment, make a further understanding of fate regulation on LSCs, and highlight its contribution to liver during pathophysiologic processes. [ABSTRACT FROM AUTHOR]

Background: Exercise plays an essential role in improving motor symptoms in Parkinson's disease (PD), but the underlying mechanism in the central nervous system remains unclear. Methods: Motor ability was observed after 12-week treadmill exercise on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. RNA-sequencing on four brain regions (cerebellum, cortex, substantia nigra (SN), and striatum) from control animals, MPTP-induced PD, and MPTP-induced PD model treated with exercise for 12 weeks were performed. Transcriptional networks on the four regions were further identified by an integrative network biology approach. Results: The 12-week treadmill exercise significantly improved the motor ability of an MPTP-induced mouse model of PD. RNA-seq analysis showed SN and striatum were remarkably different among individual region's response to exercise in the PD model. Especially, synaptic regulation pathways about axon guidance, synapse assembly, neurogenesis, synaptogenesis, transmitter transport-related pathway, and synaptic regulation genes, including Neurod2, Rtn4rl2, and Cd5, were upregulated in SN and striatum. Lastly, immunofluorescence staining revealed that exercise rescued the loss of TH+ synapses in the striatal region in PD mice, which validates the key role of synaptic regulation pathways in exercise-induced protective effects in vivo. Conclusion: SN and striatum are important brain regions in which critical transcriptional changes, such as in synaptic regulation pathways, occur after the exercise intervention on the PD model. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disease with movement and balance impairments. Although studies have reported improvement of motor symptoms with physical exercise, the mechanisms by which exercise is beneficial remains poorly understood. Our study addresses the exercise-induced changes to peripheral immune cells by interrogating the transcriptome of blood-derived leukocytes in PD patients before and after exercise. Patients attended 1 h exercise classes twice a week for 12 weeks. Leukocytes were collected at the beginning and end of the study for gene expression analysis by RNA-seq or quantitative real-time PCR. We correlated differentially expressed genes after exercise with clinical measures and analyzed the potential functions of gene changes with Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analysis. Exercise improved measures of movement and balance when compared with scores before the exercise program. Among the gene changes, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis suggests that T-cell receptor signaling, T-cell activation, and T-cell migration pathways were downregulated, while the T-cell receptor signaling pathway was the most significantly correlated with clinical measures. To further investigate T-cell-related changes in PD leukocytes, we reanalyzed the differentially expressed genes from publicly available microarray data and found that genes in the T-cell activation, differentiation, and migration pathways were upregulated in PD samples compared to controls in a time-dependent manner. Together, our findings suggest that exercise rehabilitation may improve movement and balance in PD patients by reversing the upregulated T-cell activation pathways associated with PD. This study was registered with the Chinese Clinical Trial Registry under ChiCTR-TRC-14004707. Registered on May 27, 2014. [ABSTRACT FROM AUTHOR]

Background: Muscle wasting occurs in response to various physiological and pathological conditions, including ageing and Duchenne muscular dystrophy (DMD). Transforming growth factor‐β1 (TGF‐β1) contributes to muscle pathogenesis in elderly people and DMD patients; inhibition of TGF‐β1 signalling is a promising therapeutic strategy for muscle‐wasting disorders. Hemojuvelin (HJV or Hjv as the murine homologue) is a membrane‐bound protein that is highly expressed in skeletal muscle, heart, and liver. In hepatic cells, Hjv acts as a coreceptor for bone morphogenetic protein, a TGF‐β subfamily member. The aim of this study was to investigate whether Hjv plays an essential role in muscle physiological and pathophysiological processes by acting as a coreceptor for TGF‐β1 signalling. Methods: Conventional and conditional Hjv knockout mice as well as mdx and aged mice transfected with Hjv overexpression vector were used to study the role of Hjv in muscle physiology and pathophysiology. qRT‐PCR, western blotting, and immunohistochemistry examinations were conducted to evaluate gene, protein, and structural changes in vivo and in vitro. Exercise endurance was determined using treadmill running test, and muscle force was detected by an isometric transducer. RNA interference, immunoprecipitation, and dual‐luciferase reporter assays were utilized to explore the mechanism by which Hjv regulates TGF‐β1 signalling in skeletal muscle. Results: Conventional and conditional Hjv knockout mice displayed muscle atrophy, fibrosis, reduced running endurance, and muscle force. HJV was significantly down‐regulated in the muscles of DMD patients (n = 3, mean age: 11.7 ± 5.7 years) and mdx mice as well as in those of aged humans (n = 10, 20% women, mean age: 75.1 ± 9.5 years) and mice. Overexpression of Hjv rescued dystrophic and age‐related muscle wasting. Unlike its function in hepatic cells, the bone morphogenetic protein downstream phosphorylated p‐Smad1/5/8 signalling pathway was unchanged, but TGF‐β1, TGF‐β receptor II (TβRII), and p‐Smad2/3 expression were increased in Hjv‐deficient muscles. Mechanistically, loss of Hjv promoted activation of Smad3 signalling induced by TGF‐β1, whereas Hjv overexpression inhibited TGF‐β1/Smad3 signalling by directly interacting with TβRII on the muscle membrane. Conclusions: Our findings identify an unrecognized role of HJV in skeletal muscle by regulating TGF‐β1/Smad3 signalling as a coreceptor for TβRII. Unlike the TGF‐β1/Smad3 pathway, HJV could be a reliable drug target as its expression is not widespread. Novel therapeutic strategies could potentially be devised to interfere only with the muscle function of HJV to treat DMD and age‐related muscle wasting. [ABSTRACT FROM AUTHOR]

Highlights: [•] We found that the 3′ UTR of the Fmr1 mRNA is a target of miR-130b. [•] MiR-130b suppresses the expression of Fmr1 in mouse embryonic stem cell. [•] MiR-130b alters the proliferation of mouse embryonic stem cell. [•] MiR-130b alters fate specification of mouse embryonic stem cell. [ABSTRACT FROM AUTHOR]

The role of spliceosomal intronic structures played in evolution has only begun to be elucidated. Comparative genomic analyses of fungal snoRNA sequences, which are often contained within introns and/or exons, revealed that about one-third of snoRNA-associated introns in three major snoRNA gene clusters manifested polymorphisms, likely resulting from intron loss and gain events during fungi evolution. Genomic deletions can clearly be observed as one mechanism underlying intron and exon loss, as well as generation of complex introns where several introns lie in juxtaposition without intercalating exons. Strikingly, by tracking conserved snoRNAs in introns, we found that some introns had moved from one position to another by excision from donor sites and insertion into target sties elsewhere in the genome without needing transposon structures. This study revealed the origin of many newly gained introns. Moreover, our analyses suggested that intron-containing sequences were more prone to sustainable structural changes than DNA sequences without introns due to intron's ability to jump within the genome via unknown mechanisms. We propose that splicing-related structural features of introns serve as an additional motor to propel evolution. [ABSTRACT FROM AUTHOR]

Summary The scarcity of tissue-specific stem cells and the complexity of their surrounding environment have made molecular characterization of these cells particularly challenging. Through single-cell transcriptome and weighted gene co-expression network analysis (WGCNA), we uncovered molecular properties of CD133 + /GFAP − ependymal (E) cells in the adult mouse forebrain neurogenic zone. Surprisingly, prominent hub genes of the gene network unique to ependymal CD133 + /GFAP − quiescent cells were enriched for immune-responsive genes, as well as genes encoding receptors for angiogenic factors. Administration of vascular endothelial growth factor (VEGF) activated CD133 + ependymal neural stem cells (NSCs), lining not only the lateral but also the fourth ventricles and, together with basic fibroblast growth factor (bFGF), elicited subsequent neural lineage differentiation and migration. This study revealed the existence of dormant ependymal NSCs throughout the ventricular surface of the CNS, as well as signals abundant after injury for their activation. [ABSTRACT FROM AUTHOR]