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Analysis of gene expression profiles of liver stellate cells during liver regeneration in rats.

ABSTRACT: This study performed a large-scale, high-throughput analysis of transcriptional profiling of liver stellate cells (LSCs) at the cellular level to investigate changes in the biological activity of LSCs during rat liver regeneration (LR) and the relation of these changes to LR. First, a rat liver regeneration model was established by partial hepatectomy (PH). Stellate cells were isolated in high purity and yield from the regenerating rat liver by Percoll density gradient centrifugation and immunomagnetic bead sorting. The changes in gene expression of LSCs after PH were examined using a rat genome 230 2.0 array composed of 24622 genes. The results indicated that 10241 of the 24622 genes investigated on the array were differentially expressed in LSCs. Of the 10241 genes, 1563 known genes were related to LR, which were grouped into three major gene expression clusters according to three-fold cut-off threshold: the upregulated gene cluster, the down-regulated gene cluster, and the cluster composed of genes showing complex changes in expression. Additionally, the genes were grouped into those involved in transcription regulation, signal transduction, transport, cellular metabolism, inflammation and immunity by functional analysis. When gene expression profiles were combined with the results of gene functional analysis, most of the genes involved in cytokine secretion and retinol metabolism in LSCs were significantly enriched in the cluster characterized by decreased expression, whereas genes involved in lipid metabolism were mostly enriched in the cluster showing increased expression. Based on further analysis of genes expressed in a phase-dependent manner during LR, it was suggested that lipid metabolism in LSCs was enhanced in the whole regeneration process, and that immune response and cytokine secretion were impaired during all three regenerative phases.

SUBMITTER: Xu C

PROVIDER: S-EPMC3906875 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Analysis of gene expression profiles of liver stellate cells during liver regeneration in rats.

Xu Cunshuan C Chen Xiaoguang X Chang Cuifang C Wang Gaiping G Wang Wenbo W Zhang Lianxing L Zhu Qiushi Q Wang Lei L Zhang Fuchun F

Molecules and cells 20101126 1

This study performed a large-scale, high-throughput analysis of transcriptional profiling of liver stellate cells (LSCs) at the cellular level to investigate changes in the biological activity of LSCs during rat liver regeneration (LR) and the relation of these changes to LR. First, a rat liver regeneration model was established by partial hepatectomy (PH). Stellate cells were isolated in high purity and yield from the regenerating rat liver by Percoll density gradient centrifugation and immunom ...[more]

PMID: 21191813

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Project description:Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins and formation of a fibrous scar. Hepatic stellate cells (HSCs) are the major source of collagen type 1 producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol-induced activation of human and mouse HSCs is not fully understood. We compared the gene-expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n = 3) or without underlying liver disease (n = 4) using RNA-sequencing analysis. Furthermore, the gene-expression profile of ALD hHSCs was compared with that of alcohol-activated mHSCs (isolated from intragastric alcohol-fed mice) or CCl4-activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, in addition to alcohol-activated and CCl4-activated mHSCs, share the expression of common HSC activation (Col1a1 [collagen type I alpha 1 chain], Acta1 [actin alpha 1, skeletal muscle], PAI1 [plasminogen activator inhibitor-1], TIMP1 [tissue inhibitor of metalloproteinase 1], and LOXL2 [lysyl oxidase homolog 2]), indicating that a common mechanism underlies the activation of human and mouse HSCs. Furthermore, alcohol-activated mHSCs most closely recapitulate the gene-expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely up-regulated in primary cultured alcohol-activated hHSCs and freshly isolated mHSCs, which include CSF1R (macrophage colony-stimulating factor 1 receptor), PLEK (pleckstrin), LAPTM5 (lysosmal-associated transmembrane protein 5), CD74 (class I transactivator, the invariant chain), CD53, MMP9 (matrix metallopeptidase 9), CD14, CTSS (cathepsin S), TYROBP (TYRO protein tyrosine kinase-binding protein), and ITGB2 (integrin beta-2), and other genes (compared with CCl4-activated mHSCs). Conclusion: We identified genes in alcohol-activated mHSCs from intragastric alcohol-fed mice that are largely consistent with the gene-expression profile of primary cultured hHSCs from patients with ALD. These genes are unique to alcohol-induced HSC activation in two species, and therefore may become targets or readout for antifibrotic therapy in experimental models of ALD.

Project description:BackgroundThe ability of a neuron to regenerate functional connections after injury is influenced by both its intrinsic state and also by extrinsic cues in its surroundings. Investigations of the transcriptional changes undergone by neurons during in vivo models of injury and regeneration have revealed many transcripts associated with these processes. Because of the complex milieu of interactions in vivo, these results include not only expression changes directly related to regenerative outgrowth and but also unrelated responses to surrounding cells and signals. In vitro models of neurite outgrowth provide a means to study the intrinsic transcriptional patterns of neurite outgrowth in the absence of extensive extrinsic cues from nearby cells and tissues.ResultsWe have undertaken a genome-wide study of transcriptional activity in embryonic superior cervical ganglia (SCG) and dorsal root ganglia (DRG) during a time course of neurite outgrowth in vitro. Gene expression observed in these models likely includes both developmental gene expression patterns and regenerative responses to axotomy, which occurs as the result of tissue dissection. Comparison across both models revealed many genes with similar gene expression patterns during neurite outgrowth. These patterns were minimally affected by exposure to the potent inhibitory cue Semaphorin3A, indicating that this extrinsic cue does not exert major effects at the level of nuclear transcription. We also compared our data to several published studies of DRG and SCG gene expression in animal models of regeneration, and found the expression of a large number of genes in common between neurite outgrowth in vitro and regeneration in vivo.ConclusionMany gene expression changes undergone by SCG and DRG during in vitro outgrowth are shared between these two tissue types and in common with in vivo regeneration models. This suggests that the genes identified in this in vitro study may represent new candidates worthy of further study for potential roles in the therapeutic regrowth of neuronal connections.

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Analysis of gene expression profiles of liver stellate cells during liver regeneration in rats.

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Analysis of gene expression profiles of liver stellate cells during liver regeneration in rats.

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