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Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration [scATAC-Seq]

ABSTRACT: Adult liver has enormous regenerative capacity as it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown, but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA and ATAC sequencing to map state transitions in ~ 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with immunohistochemistry, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers while others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE158873 | GEO | 2020/10/02

REPOSITORIES: GEO

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Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration [scRNA-Seq]

Project description:Adult liver has enormous regenerative capacity as it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown, but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA and ATAC sequencing to map state transitions in ~ 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with immunohistochemistry, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers while others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.

2020-10-02 | GSE158866 | GEO

Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration [ATAC-Seq]

2020-10-02 | GSE158865 | GEO

Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration [RNA-Seq]

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Survivin deficient liver of mice after partial hepatectomy

Project description:The liver possesses remarkable regenerative capacity in response to injury. Upon partial hepatectomy (PHx), terminally differentiated hepatocytes in the remaining liver enter the cell cycle and restore the liver mass and function within weeks. However, liver regeneration is often impaired in livers with chronic diseases. Survivin, an inhibitor of apoptosis protein (IAP) and member of chromosome passenger complex (CPC), plays versatile roles in cell mitosis and apoptosis. We and others found that the expression of Survivin was highly increased in liver during PHx-induced liver regeneration, which indicated that Survivin played important roles in this process. However, the function of Survivin in liver regeneration remains largely undefined. Here, using mice with genetic deletion of Survivin, we found that during PHx-induced liver regeneration Survivin regulated both hepatocyte G1/S phase transition by inhibiting the expression of p21 and G2/M phase transition by regulating the localization of CPC. Moreover, restoration of Survivin expression in Survivin-deficient hepatocytes inhibited p21 expression and promote both hepatocyte G1/S and G2/M transition during PHx-induced liver regeneration.

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Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney

Project description:Background & Aims: Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers due to its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through the complex intercellular signaling. However, the liver organogenetic mechanism, especially the role of adult hepatocytes at ectopic sites, remains unknown. In this study, we demonstrate that hepatocytes alone spurred liver organogenesis to form an organ-sized complex 3D liver that exhibited native liver architecture and functions in the kidneys of mice. Methods: Isolated hepatocytes were transplanted under the kidney capsule of monocrotaline (MCT) and partial hepatectomy (PHx)-treated mice. To determine the origin of NPCs in neo-livers, hepatocytes were transplanted into MCT/PHx-treated green fluorescent protein (GFP) transgenic mice or wild-type mice transplanted with bone marrow (BM) cells isolated from GFP mice. Results: Hepatocytes engrafted at the subrenal space of mice underwent continuous growth in response to a chronic hepatic injury in the native liver. More than 1.5 yrs later, whole organ-sized liver tissues having a greater mass than those of the injured native liver had formed. Most remarkably, we revealed that at least three types of NPCs with similar phenotypic features to the liver NPCs were recruited from the host tissues including BM. The neo-livers in the kidney exhibited liver-specific functions and architectures, including sinusoidal vascular systems, zonal heterogeneity, and emergence of bile duct cells. Furthermore, the neo-livers successfully rescued the mice with lethal liver injury. Conclusion: Our data clearly showed that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment.

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Mecp2 fine-tunes quiescence exit by targeting nuclear receptors [ChIP-Seq]

Project description:To identify the Mecp2-dependent transcriptome genome-wide during the very early stage of liver regeneration, we mapped the binding landscape of Mecp2 in control and MeCP2-KO livers before and after PHx using ChIP-seq. we mapped the binding landscape of Mecp2 in control livers before and after PHx by filtering out peaks identified in Mecp2-cKO livers. we identified a total of 14640 and 15350 Mecp2-binding genes before and after PHx in the Mecp2 control liver, respectively.

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HMGB2 is important for liver regeneration through transient accumulation of lipid droplets in hepatocytes

Project description:Liver regeneration is an well orchestrated compensatory process that regulated by multiple factors. We recently reported the importance of chromatin protein, a high-mobility group box 2 (HMGB2) in mouse liver regeneration, however, it’s molecular mechanism is not yet understood. In this study, we aimed to study how HMGB2 regulates hepatocyte proliferation during liver regeneration. Wild-type (WT) and HMGB2-knockout (KO) mice were 70% partial hepatectomized (PHx), and liver tissues were analyzed by microarray, immunohistochemistry, qPCR and western blotting. In vivo experimental findings were confirmed by in vitro experiments using HMGB2 gene knockdown in combination with de novo lipogenesis model. In WT mouse, HMGB2-positive hepatocytes were co-localized with cell proliferation markers, whereas, hepatocyte proliferation was significantly decreased in HMGB2-KO mice. Oil red-O staining detected the transient accumulation of lipid droplets at 12-24 h in WT mouse livers, however, decreased amount of lipid droplets were found in HMGB2-KO mouse livers, and it was prolonged until 36 h. Microarray, immunohistochemistry and qPCR results were demonstrated that lipid metabolism related genes were significantly decreased in HMGB2-KO mouse livers. In vitro experiments demonstrated that decreased lipid droplets in HMGB2-knockdown cells correlated with decreased cell proliferation activity. HMGB2 is involved in the regulation of liver regeneration through transient accumulation of lipid droplets in hepatocytes.

2023-10-14 | GSE244551 | GEO

Spatiotemporal expression of HMGB2 regulates cell proliferation and hepatocyte size during liver regeneration

Project description:Liver regeneration is an extraordinarily complex process involving a variety of factors; however, the role of chromatin protein in hepatocyte proliferation is largely unknown. In this study, we investigated the functional role of high-mobility group box 2 (HMGB2), a chromatin protein in liver regeneration using wild-type and HMGB2-knockout (KO) mice. Liver tissues were sampled after 70% partial hepatectomy (PHx), and analyzed by immunohistochemistry using various markers of cell proliferation, including Ki-67, PCNA, cyclin D1, cyclin B1, EdU and pH3S10. In WT mice, hepatocyte proliferation was strongly correlated with the spatiotemporal expression of HMGB2; however, cell proliferation was significantly delayed in hepatocytes of HMGB2-KO mice. Quantitative PCR demonstrated that cyclin D1 and cyclin B1 mRNAs were significantly decreased in HMGB2-KO mice livers. Interestingly, hepatocyte size was significantly larger in HMGB2-KO mice at 36-72 h after PHx, and these results suggest that hepatocyte hypertrophy appeared in parallel with delayed cell proliferation. In vitro experiments demonstrated that cell proliferation was significantly decreased in HMGB2-KO cells. A significant delay in cell proliferation was also found in HMGB2-siRNA transfected cells. In summary, spatiotemporal expression of HMGB2 is important for regulation of hepatocyte proliferation and cell size during liver regeneration.

2022-04-03 | GSE199944 | GEO

Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver

Project description:The adult liver has exceptional ability to regenerate, but how it sustains normal metabolic activities during regeneration remains unclear. Here, we use partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ~22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results reveal that following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Importantly, through combined analysis of gene regulatory networks and cell- cell interaction maps, we find that regenerating hepatocytes redeploy key developmental gene regulons, which are guided by extensive ligand–receptor mediated signaling events between hepatocytes and non-parenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferation requirements of a regenerating liver.

2021-02-01 | GSE151309 | GEO

Transcription profiling of human liver shortly after partial hepatectomy (PHx)

Project description:The liver has a remarkable ability to regenerate, with the best experimental model for regeneration being partial hepatectomy (PHx), in which up to two-thirds of the liver may be removed, and the residual lobes enlarge to make up for the missing mass in a few days’ time. Liver regeneration has been extensively studied, mainly in rodent models, and characterized in terms of transcriptional regulation of gene expression. However, little is known regarding regulation of gene expression in a human model of regeneration following PHx. We used microarrays to follow gene expression changes shortly following PHx. Experiment Overall Design: Liver tissues were collected from patients undergoing a PHx surgery (1.5, 42 and 81 years) under an IRB approval, at the onset (T0) and shortly after PHx (0.5hr, 1hr and 1.5hrs) for RNA extraction and hybridization on Affymetrix microarrays.

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