Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b

Hu, Shikai; Liu, Silvia; Bian, Yu; Poddar, Minakshi; Singh, Sucha; Cao, Catherine; McGaughey, Jackson; Bell, Aaron; Blazer, Levi L.; Wiita, Arun P.; Sidhu, Sachdev S.; Angers, Stéphane; Monga, Satdarshan P.

doi:10.1016/j.xcrm.2022.100754

Cited by 42 publications

(77 citation statements)

References 60 publications

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“…38 However, the pericentral endothelial cell-specificsecreted Wnt9b, Wnt2, and Rspo3 were shown to reprogram new hepatocytes in pericentral areas. 38,45 This was confirmed with single cell "omics," further demonstrating that Wnt agonist administration late in APAP toxicity can support rodent liver regeneration by Wnt2 and Wnt9b induction. 45 In the PHx model, regeneration is a well-organized, LSEC-driven series of events that includes the inductive phase of hepatocyte proliferation, angiogenic phase, and terminal phase.…”

Section: Zonation In Healthy Liver By Asigmentioning

confidence: 82%

“…LSECs, macrophages, and HSCs significantly contribute in the process of liver regeneration, 5,6,9,10,12,18,22,28,32,33,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] supported by scRNAseq and spatial transcriptomics studies. 55 Regeneration is studied via acute injury models such as the two-thirds partial hepatectomy model (PHx) 10 resulting in Angiocrine Signaling in the Liver Cooper et al…”

Section: Zonation In Healthy Liver By Asigmentioning

confidence: 96%

“…LSECs, macrophages, and HSCs significantly contribute in the process of liver regeneration, 5,6,9,10,12,18,22,28,32,33,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] supported by scRNAseq and spatial transcriptomics studies. 55 Regeneration is studied via acute injury models such as the two-thirds partial hepatectomy model (PHx) 10 resulting in rapid regeneration of liver mass by 96 hours postinjury or the centrilobular necrosis with acetaminophen overdose (APAP) 38 (further discussed later).…”

Section: Zonation In Healthy Liver By Asigmentioning

confidence: 96%

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Angiocrine Signaling in Sinusoidal Health and Disease

2023

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Liver sinusoidal endothelial cells (LSECs) are key players in maintaining hepatic homeostasis. They also play crucial roles during liver injury by communicating with liver cell types as well as immune cells and promoting portal hypertension, fibrosis and inflammation. Cutting-edge technology, such as single cell and spatial transcriptomics, have revealed the existence of distinct LSEC subpopulations with a clear zonation in the liver. The signals released by LSECs are commonly called “angiocrine signaling”. In this review, we summarize the role of angiocrine signaling in health and disease, including zonation in healthy liver, regeneration, fibrosis, portal hypertension, non-alcoholic fatty liver disease, alcohol-associated liver disease, aging, drug-induced liver injury, and ischemia/reperfusion, as well as potential therapeutic advances. In conclusion, sinusoidal endotheliopathy is recognized in liver disease and promising pre-clinical studies are paving the path towards LSEC-specific pharmacotherapies.

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Section: Zonation In Healthy Liver By Asigmentioning

confidence: 82%

Section: Zonation In Healthy Liver By Asigmentioning

confidence: 96%

“…LSECs, macrophages, and HSCs significantly contribute in the process of liver regeneration, 5,6,9,10,12,18,22,28,32,33,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] supported by scRNAseq and spatial transcriptomics studies. 55 Regeneration is studied via acute injury models such as the two-thirds partial hepatectomy model (PHx) 10 resulting in rapid regeneration of liver mass by 96 hours postinjury or the centrilobular necrosis with acetaminophen overdose (APAP) 38 (further discussed later).…”

Section: Zonation In Healthy Liver By Asigmentioning

confidence: 96%

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Angiocrine Signaling in Sinusoidal Health and Disease

2023

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“…Meanwhile, hepatocyte growth factor ( Hgf ) expression was enhanced in all peri-portal, mid-lobular, and peri-central LSECs, indicating that Hgf upregulation in LSECs influences hepatocyte proliferation in all regions during the repair phase of APAP toxicity. Additionally, late administration of the Wnt agonist FL6.13 stimulated liver repair and regeneration after APAP toxicity ( Hu et al, 2022 ). Because vascular Wnt ligands in peri-central LSECs are regulated by Tie1 signaling, Tie1 blockade impaired liver regeneration after partial hepatectomy via reduced levels of Wnt2 and Wnt9b ( Inverso et al, 2021 ).…”

Section: Lsecs In Liver Repairmentioning

confidence: 99%

Responses of hepatic sinusoidal cells to liver ischemia–reperfusion injury

Yoshiya

Hosono

Aoki

2023

Front. Cell Dev. Biol.

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The liver displays a remarkable regenerative capacity in response to acute liver injury. In addition to the proliferation of hepatocytes during liver regeneration, non-parenchymal cells, including liver macrophages, liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs) play critical roles in liver repair and regeneration. Liver ischemia–reperfusion injury (IRI) is a major cause of increased liver damage during liver resection, transplantation, and trauma. Impaired liver repair increases postoperative morbidity and mortality of patients who underwent liver surgery. Successful liver repair and regeneration after liver IRI requires coordinated interplay and synergic actions between hepatic resident cells and recruited cell components. However, the underlying mechanisms of liver repair after liver IRI are not well understood. Recent technological advances have revealed the heterogeneity of each liver cell component in the steady state and diseased livers. In this review, we describe the progress in the biology of liver non-parenchymal cells obtained from novel technological advances. We address the functional role of each cell component in response to liver IRI and the interactions between diverse immune repertoires and non-hematopoietic cell populations during the course of liver repair after liver IRI. We also discuss how these findings can help in the design of novel therapeutic approaches. Growing insights into the cellular interactions during liver IRI would enhance the pathology of liver IRI understanding comprehensively and further develop the strategies for improvement of liver repair.

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“…Random DNA-labeling revealed that only 1.9% hepatocytes divided more than once in 8 to 10 months (Miyajima et al 2014). However, the liver possesses an exceptional ability to regenerate rapidly following partial hepatectomy, enabling surgical resection of a portion of the liver as well as living donor and segmented liver transplantation (Hu et al 2022). Recent evidence suggests that hepatocytes proliferate randomly in all hepatic regions to maintain homeostasis (Chen, Jimenez, et al 2020).…”

mentioning

confidence: 99%

Machine learning and single cell RNA sequencing analysis identifies regeneration-related hepatocytes and highlights a Birc5-related model for identifying cell proliferative ability

Jian

Wang

et al. 2023

Preprint

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Background Partial hepatectomy (PHx) has been shown to induce rapid regeneration of adult liver under emergency conditions. Therefore, an in-depth investigation of the underlying mechanisms that govern liver regeneration following PHx is crucial for a comprehensive understanding of this process. Method We analyzed scRNA-seq data from liver samples of normal and PHx-48-hour mice and identified a population of highly proliferative hepatocytes 48 hours after hepatectomy. Seven machine learning algorithms were utilized to screen and validate a gene signature that accurately identifies and predicts this population. We also used co-immunostaining of zonal markers with BIRC5 to investigate regional characteristics of hepatocytes post-PHx. Results Single cell sequencing results revealed a population of regeneration-related hepatocytes. Of note, transcription factor analysis emphasized the importance of Hmgb1 transcription factor in liver regeneration. HdWGCNA and machine learning algorithm screened and obtained the key signature characterizing this population, including a total of 17 genes, most of which have been confirmed to be related to liver regeneration, and the function enrichment analysis indicated their high correlation with cell cycle pathway. Furthermore, we found that the spatial characteristics of hepatocytes gradually weakened during regeneration and immunostaining further revealed that those hepatocytes with active proliferative ability primarily initiate in the midlobular zone and then repopulated peripheral region. It is note-worthy that we inferred that Hmgb1 might be vital in the regeneration-related hepatocytes of PHx_48h group. Parallelly, Birc5 might be closely related to the regulation of liver regeneration, and positively correlated with Hmgb1 while negatively correlated with portal vein and central vein characteristics. Conclusions Our study has identified a distinct population of hepatocytes that are closely associated with liver regeneration. Through machine learning algorithms, we have identified a set of 17 genes that are highly indicative of the regenerative capacity of hepatocytes. This gene signature has enabled us to assess the proliferation ability of in vitro cultured hepatocytes using sequencing data alone. Furthermore, our findings suggest that Birc5 may play a crucial role in regulating the proliferative potential of hepatocytes.

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Single-cell spatial transcriptomics reveals a dynamic control of metabolic zonation and liver regeneration by endothelial cell Wnt2 and Wnt9b

Cited by 42 publications

References 60 publications

Angiocrine Signaling in Sinusoidal Health and Disease

Angiocrine Signaling in Sinusoidal Health and Disease

Responses of hepatic sinusoidal cells to liver ischemia–reperfusion injury

Machine learning and single cell RNA sequencing analysis identifies regeneration-related hepatocytes and highlights a Birc5-related model for identifying cell proliferative ability

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