A single-cell RNA-Seq of human hepatocyte-derived liver progenitor-like cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116113 | GEO | 2018/06/22
REPOSITORIES: GEO
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Project description:Hepatocyte-derived liver progenitor-like cells (HepLPCs) can reversibly differentiate into mature hepatocytes and play important roles in liver regeneration following acute liver failure. However, the mechanisms by which HepLPCs exert these regulatory effects are unclear. Herein, we report that HepLPCs participate in reinitiating liver regeneration and improving survival during acute liver failure, at least in part, via miRNA-183-5p, which is released from HepLPCs in extracellular vesicles. Thus, these findings may identify novel targets and strategies for the treatment of acute liver failure.
2024-12-06 | GSE226645 | GEO
Project description:Cell therapy shows great promise as an alternative therapy for the cirrhotic liver. We have previously developed an approach for efficient expansion of both murine and human hepatocyte-derived liver progenitor-like cells (HepLPCs) in vitro without genetic modification. The current study aimed to apply HepLPCs to treatment of liver cirrhosis. The effects of allogeneic HepLPCs transplantation were studied in rat models of liver cirrhosis induced by carbon tetrachloride (CCl4) . Liver tissues were collected and analyzed by RNA sequencing array to analyze changes in histology or gene expression patterns. Transplantation of HepLPCs reduced active fibrogenesis and net fibrosis in model of liver cirrhosis. Apoptosis of hepatic stellate cells (HSCs) was observed in vivo after HepLPCs treatment.
2024-04-10 | GSE200550 | GEO
Project description:The escalating demand for liver transplantation, coupled with the scarcity of donor organs and inherent transplantation risks, underscores the urgent need for innovative cirrhosis treatments. To address this, we have developed a protocol for transforming human primary hepatocytes into expandable Hepatocyte-Derived Liver Progenitor-Like Cells (HepLPCs). In animal models, these cells exhibited anti-fibrotic properties and facilitated liver regeneration. This study comprises a pre-clinical phase and an inaugural clinical trial involving nine cirrhosis patients to assess the feasibility and safety of HepLPC treatment. The HepLPCs infusion was well-tolerated, devoid of transfusion reactions or dose-limiting toxicities. Primary outcome measures, encompassing safety and feasibility, were successfully met. Notably, the results revealed enhanced liver function following HepLPCs infusion, indicating significant improvements in cirrhosis indicators over a 6-month observation period. These promising findings advocate for the therapeutic potential of HepLPCs as an innovative strategy for liver cirrhosis, warranting further exploration through clinical trials, particularly in decompensated cirrhosis and acute-on-chronic liver failure patients.
2024-12-30 | GSE248227 | GEO
Project description:Administration of soluble molecules to induce endogenous adult liver progenitor-like cells may provide a clinically and effectively applicable approach for liver damage repair. Here, we report that HGF in combination with a cocktail of small molecules Y-27632, A-83-01, and CHIR99021 (HACY), which we have previously defined to convert mature hepatocytes (MHs) to liver progenitor-like cells (HepLPCs) in vitro, could induce the replenishment of endogenous HepLPCs and relieve chronic liver dysfunction during persistent injury. The liver progenitor cells surface marker, CD24, was found to be highly expressed in HepLPCs in vitro. Similarly, injection of HACY into mice with carbon tetrachloride (CCL4) treatment also induced conversion of mature hepatocytes to CD24+ progenitor-like cells in vivo, leading to the attenuation of liver fibrosis. Compared to the liver progenitor cells (LPCs) derived from nonparenchymal cells, HACY-induced CD24+ HepLPCs retained an increased hepatic function by RNA sequencing analysis and could promote restoration of liver function by replacing CCL4-impaired liver cells during chronic hepatic damages. And CD24+ liver stem cells could also be observed in human liver fibrosis tissues and expanded in 3D hepatic spheroid in the present of HACY. Together, the results of our study indicated that injection of a cocktail of HACY might be a valuable multiple targets therapy for patients with chronic liver fibrotic pathologies.
2019-07-01 | GSE125095 | GEO
Project description:The cellular source for hepatocyte transplantation and liver regeneration in chronically hepatic diseases is a fundamental topic in liver biology. A successful therapeutic approach based on a benificial stem/progenitor cells would involve replacing damaged cells or restoring homeostasis to the areas that underlie the fibrotic response. This study aims to isolate and culture hepatocyte and non-parenchymal cells derived liver progenitor-like cells (HepLPCs and NPC-LPCs) to identify a beneficial cell sources for cell-based therapy against chronic liver injury. Two types of lineage tracing models including tdTomato mice with AAV8-TBG-Cre and AlbCreERT/R26GFP were purified for hepatocytes and non-parenchymal cells respectively, and cultured for transition to progenitor-like cells (LPCs) in TEM. The differences between them were clarified by RNA sequencing, suggesting that HepLPCs retaining basal levels of hepatic function and transcription factors (TFs), including Foxa3. Organoids and 3D hepatic spheroids culturing systems were used for further analysis of bile duct and hepatic functioning diversity. When transplanting in mice with CCL4 treatment, HepLPCs displayed the characteristics of TFs regulatory reactivation and physiological balance restoration, resulting in a significant improvement in liver fibrosis compared with NPC-LPCs, which are crucial for liver regeneration in the treatment of patients with a broad range of hepatic fibrosis.
2020-07-30 | GSE135951 | GEO
Project description:Improvement of liver cirrhosis using hepatocyte-derived liver progenitor-like cells (HepLPCs): a prospective, open label, single arm, safety trial
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Project description:Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease; yet the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely under-stood. Using a cell type-resolved genomics approach, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a partial loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a net-work of NASH-activated transcription factors (TFs), as exemplified by Elf3 and Glis2. Indeed, Elf3 and Glis2 controlled hepatocyte identity and fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell (HSC) gene programs. Thus, interconnected TF networks not only promoted hepatocyte dysfunction, but also directed the intra-hepatic crosstalk with HSCs necessary for NASH and fibrosis progression implying molecular “hub-centered” targeting strategies to be superior to existing mono-target approaches as currently used in NASH therapy.
2021-07-13 | PXD025691 | Pride
Project description:We previously showed that severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in the hepatic response to injury remains a contentious topic. We have now used genetic lineage tracing of Hnf1β-expressing biliary duct cells to assess their contribution to LPC expansion and hepatocyte generation during normal liver homeostasis, and following different types of liver injury. We found that ductular reaction cells in human cirrhotic livers express HNF1β. However, HNF1β expression was not present in newly generated EpCAM-positive hepatocytes. Using a tamoxifen-inducible Hnf1βCreER/R26RYFP/LacZ mouse, we show that there is no contribution of the biliary epithelium to hepatocyte turnover during liver homeostasis in healthy mice. Moreover, after loss of liver mass, Hnf1β+ LPC did not contribute to hepatocyte regeneration. We also assessed the contribution of Hnf1β+ cells following acute and repeated liver injury. All animal models showed expansion of LPC, as assessed by immunostaining and gene expression profile of sorted YFP-positive cells. A contribution of Hnf1β+ LPC to hepatocyte generation was not detected in animal models of liver injury with preserved hepatocyte regenerative potential such as acute acetaminophen, carbon tetrachloride injury, or chronic diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet. However, in mice fed with choline-deficient ethionine-supplemented (CDE)-diet, which causes profound hepatocyte damage and arrest, a small number of hepatocytes were derived from Hnf1β+ cells. Conclusion: Hnf1β+ cells do not participate in hepatocyte turnover in the healthy liver or during liver regeneration after partial hepatectomy. After liver injury, LPC arise from the biliary duct epithelium, which gives rise to a limited number of hepatocytes only when hepatocyte regeneration is compromised. Transcriptomic profile using MoGeneST-2.0 chip from 3 samples of YFP+ CDE, 3 samples of YFP+ DDC, 2 samples of YFP+ UTR and 3 samples YFP-
2016-07-03 | E-GEOD-51389 | biostudies-arrayexpress
Project description:We previously showed that severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in the hepatic response to injury remains a contentious topic. We have now used genetic lineage tracing of Hnf1β-expressing biliary duct cells to assess their contribution to LPC expansion and hepatocyte generation during normal liver homeostasis, and following different types of liver injury. We found that ductular reaction cells in human cirrhotic livers express HNF1β. However, HNF1β expression was not present in newly generated EpCAM-positive hepatocytes. Using a tamoxifen-inducible Hnf1βCreER/R26RYFP/LacZ mouse, we show that there is no contribution of the biliary epithelium to hepatocyte turnover during liver homeostasis in healthy mice. Moreover, after loss of liver mass, Hnf1β+ LPC did not contribute to hepatocyte regeneration. We also assessed the contribution of Hnf1β+ cells following acute and repeated liver injury. All animal models showed expansion of LPC, as assessed by immunostaining and gene expression profile of sorted YFP-positive cells. A contribution of Hnf1β+ LPC to hepatocyte generation was not detected in animal models of liver injury with preserved hepatocyte regenerative potential such as acute acetaminophen, carbon tetrachloride injury, or chronic diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet. However, in mice fed with choline-deficient ethionine-supplemented (CDE)-diet, which causes profound hepatocyte damage and arrest, a small number of hepatocytes were derived from Hnf1β+ cells. Conclusion: Hnf1β+ cells do not participate in hepatocyte turnover in the healthy liver or during liver regeneration after partial hepatectomy. After liver injury, LPC arise from the biliary duct epithelium, which gives rise to a limited number of hepatocytes only when hepatocyte regeneration is compromised.
2016-01-01 | GSE51389 | GEO
Project description:We performed single-cell RNA sequencing (scRNA-seq) analysis using clinical samples of PLC patients. We first generated scRNA-seq profiles of freshly isolated PLC from patients with 10x Genomics. A total of 25,189 single-cell transcriptomes from tumors of two patients were obtained after initial quality controls.
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