Temporal Analyses of Postnatal Liver Development and Maturation by Single Cell Transcriptomics

Liang, Yan; Kaneko, Kota; B, Xin; J, Lee; X, Sun; Zhang, K; Feng, Gen‐Sheng

doi:10.1101/2021.07.14.451852

Cited by 5 publications

(12 citation statements)

References 72 publications

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“…We further validated these differences between normal neonatal and adult HSCs using the scRNA‐seq data generated by a recent study on mouse liver postnatal development (Figure ). [ 28 ]…”

Section: Resultsmentioning

confidence: 99%

A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis

et al. 2022

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Background and Aims Hepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigate whether the neonatal liver provides a protumorigenic niche to HB development. Approach and Results HB development was compared between orthotopic transplantation models established in postnatal day 5 (P5) and 60 (P60) mice (P5Tx and P60Tx models). Single‐cell RNA‐sequencing (sc‐RNAseq) was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. Conclusions We found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc‐RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor‐surrounding liver that express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout (KO) in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in tumors from patients with metastatic HB, there was a similar larger population of aHSCs in the tumor‐surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with prognosis of patients with HB among pediatric cancers. We demonstrated that the neonatal liver provides a prometastatic niche to HB development through the Cxcl1/Cxcr2 axis.

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“…We further validated these differences between normal neonatal and adult HSCs using the scRNA‐seq data generated by a recent study on mouse liver postnatal development (Figure ). [ 28 ]…”

Section: Resultsmentioning

confidence: 99%

A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis

et al. 2022

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“…Cd74 + /Clec9a + /H2- Aa + /Irf8 + /Siglech + /Runx2 + /CD7 + Dendritic cells (DCs), F13a1 + /S100a6 + /Ly6c2 + Macrophages, Mpo + /Elane + /Prtn3 + /Fcnb + /Ngp + /Chil3 + Neutrophil progenitors I and II, Cd177 + /Stfa2 +/ Mmp8 + /Asprv1 + Neutrophils, Mcpt8 + /Gata2 + /Cpa3 + Mast cells; ii) the Lymphoid lineage Ltb + /Igll1 + /Il7r + /Cd19 + /Ebf1 + /Igkc +/ Cd79a/b + B-cells; and iii) Erythroid cells including Car1 + /Gata1 + /Klf1 + progenitors, Mt2 + /Tfrc + /Slc4a1 + /Hemgn + Erythroblasts, Gypa + /Bpgm + /Hba-a2 + Erythrocytes, and Itga2b + (Cd41 + )/Treml1 + /Pf4 + Megakaryocytes. The scRNA seq also revealed the presence of population of Ncr1 + /Gzma + /Tbx21 + NK(T) cells, coming from both fetal thymus and liver [4,[75][76][77][78] (Fig. 2B, C).…”

Section: Comprehensive Single Cell Analysis Identifies a Reduction In...mentioning

confidence: 86%

“…How the pediatric liver responds to cholestasis during the pediatric hematopoietic to metabolic shift [2,4] is poorly understood. In the adult cholestatic liver, bile acids activate hepatocytes, which then secrete cytokines to attract lymphocytes [81].…”

Section: Delayed Hepatocyte Maturation and Diminished Hepatocyte Acti...mentioning

confidence: 99%

Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

Mašek

Filipovic

Hankeová³

et al. 2022

Preprint

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Background and Aims: Alagille syndrome (ALGS) is a pediatric genetic disorder, caused by mutations in the Notch ligand JAGGED1, presenting with cholestasis due to intrahepatic bile duct paucity. Despite chronic liver disease, few patients develop severe fibrosis or liver cancer, compared to other chronic liver diseases. In contrast, about 1/3 of ALGS patients suffer from reoccurring infections. Notch signaling regulates both liver and immune system development, but how immune system defects interact with liver pathology in ALGS to influence disease course is not known. Here, we aimed to determine whether a mouse model of ALGS mimics fibrosis and liver cancer, and whether ALGS immune system compromise could positively modulate inflammation or liver disease course. Methods: We used single cell RNA sequencing and 25-color flow cytometry to characterize cell populations in embryonic and postnatal liver in an ALGS mouse model (Jag1Ndr/Ndr mice). We analyzed liver cancer prevalence in Jag1Ndr/Ndr mice, in a cancer-prone genetic background, and thymic and spleen cell composition using flow cytometry. Finally, to test the functionality of the Jag1Ndr/Ndr immune system we performed adaptive immune cell transfer experiments into Rag1-/- mice and assessed inflammatory capacity in an ulcerative colitis model and in a DDC model of hepatocellular damage. Results: Adult Jag1Ndr/Ndr mice do not develop liver tumors (0%) while 45% of control mice do. Interestingly, Jag1Ndr/Ndr mice display ALGS-like chicken-wire hepatocellular fibrosis concomitant with mild inflammation shortly after the onset of liver cholestasis. Comprehensive single cell analysis revealed that liver CD4+ and CD8+ T cells of Jag1Ndr/Ndr mice are dysregulated in favor of CD4+, and Regulatory T-cells (Tregs) manifest reduced activation. Trans-plantation experiments show no difference between Jag1Ndr/Ndr and Jag1+/+ lymphocytes in DDC-induced liver damage. In contrast, Jag1Ndr/Ndr lymphocytes do not mount an inflammatory response to bacterial infection. Conclusion: Here we report immune dysregulation and cancer protection in the hypomorphic Jag1 mouse model of ALGS. Disrupted thymocyte differentiation coincides with limited activation of hepatocytes, blunting the inflammatory response to cholestasis. This may contribute to the pericellular fibrosis and prevent carcinogenesis. These results prompt the question of the relative contribution of Jag1 to liver cell pathology vs immune system in ALGS and high-light the need of future studies focused on dissecting apart how Jag1 modulates susceptibility to infection versus cancer risk.

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“…Different from whole-tissue RNA sequencing analysis, scRNA-seq, spatial transcriptomics, and emerging single-cell multimodal omics endowed the study of transcriptional activity at the single-cell or spatial level, further broadening our understanding of tissue-cell interaction in situ-for example, under physiological conditions, scRNA-seq analyzed the livers of mice at 1, 3, 7, 21, and 56 days after birth and identified myeloid cell subsets at different time points, including a unique source of Dcn + Mac from day 7 (11). At these periods, there was a stable Wnt signal in the interaction between KCs and hepatocytes, but a unique NOV-NOTCH1 signal interaction was produced in D7.…”

Section: Vistamentioning

confidence: 99%

“…Extensive mouse and human research have shown that neutrophils and macrophages exert a pivotal part in the foundation, development, and reversion of liver diseases, including in guiding tissue remodeling. With the progress of technology, more and more myeloid cell subtypes have been identified and located by single-cell multimodal omics (8)(9)(10)(11)(12). Each myeloid type acts as a unique individual participating in the immune response.…”

Section: Introductionmentioning

confidence: 99%

Myeloid cells in alcoholic liver diseases: Mechanism and prospect

Chen

et al. 2022

Front. Immunol.

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Alcoholic liver disease (ALD) is a leading chronic liver disease in which immune cells play a vital role. Myeloid cells have been extensively studied in ALD, including granulocytes, macrophages, monocytes, and dendritic cells, which are involved in the occurrence and progression of steatosis, inflammation, fibrosis, and eventual cirrhosis. These cells can be popularly targeted and regulated by factors from different sources, including cytokines secreted by other cells, extracellular vesicles, and substances in serum—for example, infiltration of monocytes or neutrophils, activation of Kupffer cells, and polarization of macrophages. These processes can affect and change the function and phenotype of myeloid cells. Here we mainly review the key mediators that affect the infiltration and function of mainly myeloid cells in ALD as well as their regulatory mechanisms on target cells, which may provide novel immunotherapeutic approaches. The single-cell multimodal omics of myeloid cells is also discussed to help transform them into basic research or therapeutic strategy of ALD clinically.

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Temporal Analyses of Postnatal Liver Development and Maturation by Single Cell Transcriptomics

Cited by 5 publications

References 72 publications

A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis

A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis

Jag1 Insufficiency Disrupts Neonatal T Cell Differentiation and Impairs Hepatocyte Maturation, Leading to Altered Liver Fibrosis

Myeloid cells in alcoholic liver diseases: Mechanism and prospect

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