• CAR T cells
• CSC-targeted therapies
• breast cancer
• cancer stem cells
• immunological profile
• immunotherapy
• vaccines

• Humans
• Breast Neoplasms/immunology
• Breast Neoplasms/therapy
• Neoplastic Stem Cells/immunology
• Immunotherapy/methods
• Female
• Signal Transduction
• Cancer Vaccines/therapeutic use

• MSCs
• animal studies
• neurological diseases

• Humans
• Nervous System Diseases/therapy
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cell Transplantation/methods
• Animals
• Cell- and Tissue-Based Therapy/methods
• Clinical Trials as Topic
• Cell Differentiation

• KKE19011A Fujian Provincial Department of Agriculture

• Cell therapy
• Feeder layer
• Feeder-free systems
• Pluripotent stem cells
• Reprogramming
• Self-renewal

• Animals
• Pluripotent Stem Cells
• Feeder Cells/metabolism
• Regenerative Medicine
• Tissue Engineering

• CD203c
• antigens
• endothelial cells
• fetal cells
• hepatoblastoma
• hepatoblasts
• hepatology
• leukocytes

• assisted reproductive technology
• cancer risk factors
• epidemiology
• in vitro fertilization
• liver cancer
• osteosarcoma
• pediatric cancer

• Pregnancy
• Female
• Adolescent
• Child
• Humans
• Birth Weight
• Premature Birth/etiology
• Hepatoblastoma
• Cross-Sectional Studies
• Reproductive Techniques, Assisted/adverse effects
• Osteosarcoma
• Liver Neoplasms/complications
• Bone Neoplasms/complications

• T32 GM007171 NIGMS NIH HHS
• T32 GM145449 NIGMS NIH HHS
• Alex's Lemonade Stand Foundation for Childhood Cancer

• C3G
• epithelial mesenchymal transition
• migration
• oval cells
• stemness

• DMSO
• HepaRG cells
• gene expression
• hepatic differentiation
• histone modification

• Dimethyl Sulfoxide/metabolism
• Dimethyl Sulfoxide/pharmacology
• Epigenesis, Genetic
• Hepatocyte Nuclear Factor 1-alpha/metabolism
• Hepatocyte Nuclear Factor 4/metabolism
• Hepatocytes/drug effects
• Hepatocytes/metabolism
• Humans
• Liver/metabolism
• PPAR alpha/metabolism

• Differentiation
• Hepatic stem/progenitor cells
• Isolation
• Proliferation
• Surface markers

The primary epithelial tumors of the liver (PETL) are composed of a series of heterogeneous tumors. Although the classification of PETLs has been updated several times by the World Health Organization, the cellular origins of some tumors in this family remain to be precisely depicted. In addition, certain tumors in different categories have similar histology, molecular phenotypes and biological characteristics, suggesting that they may have the same cellular origin. In this work, a narrative review method was adopted to review the relevant papers. By comparing the expression profiles of biomarkers of liver epithelium at different lineages and stages of differentiation, the cells-of-origin of some major members of the PETL family were reassessed. We propose that 1) hepatic adenomas, hepatocellular carcinomas (HCCs) and pure fetal hepatoblastomas (HBs) share the same spectrum in their cellular origin including the hepatocytic-committed progenitors (HCP) and their differentiated descendants. 2) Bile duct adenomas, peribiliary cysts and intrahepatic cholangiocellular carcinomas (ICCs) can share the same spectrum in their cellular origin including the cholangiocytic-committed progenitors (CCP) and their differentiated descendants. 3) The cells-of-origin of embryonal HBs include liver stem cells (LSCs), hepatoblasts, and transitional cells between them. Embryonal HB with small cell element, small cell undifferentiated HB and small cell neuroendocrine carcinoma of the liver can have the same or similar cells-of-origin from LSC. Embryonal HB lacking the small cell component of the LSC phenotype and presenting both hepatocytic and bile duct/ductule components may originate from actual hepatoblasts/hepatic progenitor cells (HPCs) as the combined HCC-ICC does. 4) Teratoid hepatoblastoma and mixed epithelial/mesenchymal HBs can be derived from the LSCs or even less committed extrahepatic pluripotent stem cell. 5) Many members of the PETLs family, including those derived from LSCs, hepatoblasts/HPCs, early HCPs and CCPs, have neuroendocrine potentiality. Except for those primary hepatic neuroendocrine tumor (PHNET) exhibit hepatocytic and/or cholangiocytic phenotypes, other PHNETs subtype may be derived from the descendants of LSC that differentiate towards the upper digestive tract, pancreas or other lineages.

Human liver stem cells (HLSCs) were described for the first time in 2006 as a new stem cell population derived from healthy human livers. Like mesenchymal stromal cells, HLSCs exhibit multipotent and immunomodulatory properties. HLSCs can differentiate into several lineages under defined in vitro conditions, such as mature hepatocytes, osteocytes, endothelial cells, and islet-like cell organoids. Over the years, HLSCs have been shown to contribute to tissue repair and regeneration in different in vivo models, leading to more than five granted patents and over 15 peer reviewed scientific articles elucidating their potential therapeutic role in various experimental pathologies. In addition, HLSCs have recently completed a Phase 1 study evaluating their safety post intrahepatic injection in infants with inherited neonatal onset hyperammonemia. Even though a lot of progress has been made in understanding HLSCs over the past years, some important questions regarding the mechanisms of action remain to be elucidated. Among the mechanisms of interaction of HLSCs with their environment, a paracrine interface has emerged involving extracellular vesicles (EVs) as vehicles for transferring active biological materials. In our group, the EVs derived from HLSCs have been studied in vitro as well as in vivo. Our attention has mainly been focused on understanding the in vivo ability of HLSC–derived EVs as modulators of tissue regeneration, inflammation, fibrosis, and tumor growth. This review article aims to discuss in detail the role of HLSCs and HLSC-EVs in these processes and their possible future therapeutic applications.

• acute kidney injury
• acute liver injury
• chronic kidney disease
• chronic liver disease
• extracellular vesicles
• hepatic stem cells
• liver regeneration
• renal regeneration

• Cancer stem cell
• Epithelial-to-mesenchymal transition
• Liver cancer
• Microvesicles

CD326 has been used as a single marker to enrich for hepatic stem cell populations in the liver. However, bile duct epithelium is also positive for CD326, which impedes the selection of pure hepatic stem cell populations. Some markers have been proposed to be co-expressed by hepatic stem cells but these have not been systematically compared. Therefore, we determined the percentages and compared the characteristics of human liver cells expressing potential stem cell surface markers.

We analyzed CD326 expression in human liver tissues from fetal, neonatal, pediatric, and adult stages using immunohistochemistry. In flow cytometry, we quantified fetal liver cells for their co-expression of CD326 with CD56, CD117, CD44, CD90, CD49f, LGR5 and SSEA4. We analyzed the various fractions for their quantitative expression of genes typically associated with progenitors and hepatic lineages.

12.5% of cells were positive for CD326; of these, 63.5% co-expressed CD44. The lowest co-expression percentages were for SSEA4 (2.1%) and LGR5 (0.7%). Fractions revealed distinct gene expression patterns. Of all combinations, cells that co-expressed surface CD326 and SSEA4 demonstrated the highest gene expression for the proliferation marker MKi67 and hepatic markers DLK1, AFP and ALB, and were the only fraction negative for the biliary epithelial marker KRT19. Histology of adult and fetal liver showed cells positive for CD326 and SSEA4 but negative for CK19.

CD326-positive cells represent a heterogeneous population, which in combination with SSEA4 potentially distinguishes bile duct epithelium from hepatic stem cells. These findings can help to further classify human hepatic progenitor stages.

• CD326
• EPCAM
• epithelial cell adhesion molecule
• hepatic stem cell
• liver

• allogeneic hematopoietic stem cell transplantation
• graft versus host disease
• multipotent mesenchymal stromal cells

• Agar/PVA nanofibers
• differentiation
• self-renewal
• spermatogonial stem cells
• three dimensional culture

Several markers have been reported to be specific for hepatic cancer stem cells (HCSCs), which is usually thought to be highly associated with poor clinical outcomes. Tumor-infiltrating immune cells act as an important factor for oncogenesis. Little is known about the correlation of HCSC markers to prognosis and immune infiltrates.

Expression of HCSC markers was analyzed through Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA) and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), respectively. The prognostic effect of HCSC markers was evaluated using Kaplan-Meier plotter in association with different tumor stages, risk factors, and gender. The correlation of HCSC markers to tumor-infiltrating immune cells was tested by Tumor Immune Estimation Resource (TIMER). HCSC markers related gene sets were investigated by GEPIA, with their biological functions being analyzed by Cytoscape software.

The expression level of 10 HCSC markers in HCC was higher than that in normal tissues in at least one database. Among them, high expression of CD24, SOX9, and SOX12 was positively correlated with poor prognosis (CD24: OS P = 0.0012, PFS P = 7.9E–05. SOX9: OS P = 0.012. SOX12: OS P = 0.0004, PFS P = 0.0013, respectively). However, the expression of CD13, CD34 and ALDH1A1 was associated with prolonged OS and PFS. SOX12 was significantly upregulated in poor prognosis of HCC patients with different conditions. Besides, total nine HCSC markers were identified to be positively associated with immune infiltration, including SOX12. Furthermore, Toll-like receptor signaling pathway was found to be one major pathway of these HCSC markers related gene networks.

Our results suggest that seven upregulated HCSC markers (CD90, EpCAM, CD133, CD24, SOX9, CK19, and SOX12) are related with poor prognosis and immune infiltration in HCC. In addition, we find that high SOX12 expression remarkably affect prognosis in male HCC patients but not in female. HCC patients under viral infection or alcohol intake with increased SOX12 expression had poorer prognosis. Therefore, HCSCs markers likely play an important role in tumor related immune infiltration and SOX12 might be a potential therapeutic target in patients with HCC.

• cancer stem cell
• hepatocellular carcinoma
• immune infiltrates
• prognostic biomarker

• Cancer stem cell
• Digestive cancer
• Prognosis

• ductular reaction
• liver cancer
• liver regeneration
• liver stem cell
• oval cell

• Adult Stem Cells/physiology
• Animals
• Cell Differentiation
• Cell Plasticity/physiology
• End Stage Liver Disease/etiology
• End Stage Liver Disease/physiopathology
• Hepatocytes/physiology
• Humans
• Liver/injuries
• Liver/physiology
• Liver Diseases/physiopathology
• Regeneration/physiology
• Stem Cells/physiology

• R01 DK116993 NIDDK NIH HHS
• T32 EB001026 NIBIB NIH HHS
• R01 DK062277 NIDDK NIH HHS
• P30 DK120531 NIDDK NIH HHS
• R01 DK100287 NIDDK NIH HHS
• R01 CA204586 NCI NIH HHS
• F31 DK115017 NIDDK NIH HHS

• biomaterial
• cell
• encapsulation
• liver tissue engineering (LTE)
• scaffold

• liver cirrhosis
• liver fibrosis

• Animals
• Disease Models, Animal
• Fetus
• Heterografts
• Humans
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Cirrhosis/therapy
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mice, Transgenic
• Stem Cell Transplantation
• Stem Cells/metabolism
• Stem Cells/pathology

• National University Health System (NUHS/NCSP-R)

• Ductular reaction
• Fibroblast
• Fibrosis
• Senescence
• Transforming growth factor beta 1

• ATP Binding Cassette Transporter, Subfamily B/genetics
• Animals
• Biomarkers
• Cell Line
• Cholangitis, Sclerosing/diagnosis
• Cholangitis, Sclerosing/genetics
• Cholangitis, Sclerosing/metabolism
• Disease Models, Animal
• Epithelial Cells/metabolism
• Epithelial-Mesenchymal Transition/genetics
• Fibrosis
• Gene Knockdown Techniques
• Liver/metabolism
• Liver/pathology
• Male
• Mice
• Mice, Knockout
• Phenotype
• Vimentin/genetics
• ATP-Binding Cassette Sub-Family B Member 4

• R21 AA025157 NIAAA NIH HHS
• R21 AA025997 NIAAA NIH HHS
• R01 DK107310 NIDDK NIH HHS
• I01 BX000574 BLRD VA
• IK6 BX004601 BLRD VA
• R01 DK108959 NIDDK NIH HHS
• K01 AA026385 NIAAA NIH HHS
• R01 DK110035 NIDDK NIH HHS
• R01 DK054811 NIDDK NIH HHS
• I01 BX001724 BLRD VA
• R01 DK076898 NIDDK NIH HHS

The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human foetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of foetal liver and maintain a transcriptional profile distinct from foetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogeneity within the EpCAM⁺ population of freshly isolated foetal and adult human liver identifies diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolate foetal HHyPs and confirm their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenchymal populations, including mature BECs, by distinct gene expression profiles.

The liver parenchyma consists of several cell types, but the origin of this tissue in humans is unclear. Here, the authors perform single cell RNA sequencing of human fetal and adult liver to identify a hepatobiliary hybrid progenitor population of cells, which have a similar gene signature to mouse oval cells.

• Graft-versus-host disease
• Mesenchymal stem cells
• Meta-analysis
• Stem cell transplantation

• Animals
• Graft vs Host Disease/prevention & control
• Graft vs Host Disease/therapy
• Hematopoietic Stem Cell Transplantation/methods
• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/physiology

• National Natural Science Foundation of China
• National Key Research and Development Program of China

• EMT
• HGF/c-Met
• Oval cell
• TGF-β

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly cancers worldwide. Therefore, current global research focuses on molecular tools for early diagnosis of HCC, which can lead to effective treatment at an early stage. Perilipin 5 (PLIN5) has been studied as one of the main proteins of the perilipin family, whose role is to maintain lipid homeostasis by inhibiting lipolysis. In this study, we show for the first time that PLIN5 is strongly expressed in tumors of human patients with HCC as well as in mouse livers, in which HCC was genetically or experimentally induced by treatment with the genotoxic agent diethylnitrosamine. Moreover, the secreted acute phase glycoprotein Lipocalin 2 (LCN2) established as a biomarker of acute kidney injury, is also proven to indicate liver injury with upregulated expression in numerous cases of hepatic damage, including steatohepatitis. LCN2 has been studied in various cancers, and it has been assigned roles in multiple cellular processes such as the suppression of the invasion of HCC cells and their metastatic abilities. The presence of this protein in blood and urine, in combination with the presence of α-Fetoprotein (AFP), is hypothesized to serve as a biomarker of early stages of HCC. In the current study, we show in humans and mice that LCN2 is secreted into the serum from liver cancer tissue. We also show that AFP-positive hepatocytes represent the main source for the massive expression of LCN2 in tumoral tissue. Thus, the strong presence of PLIN5 and LCN2 in HCC and understanding their roles could establish them as markers for diagnosis or as treatment targets against HCC.

• AFP
• HCC
• LCN2
• PLIN5
• cancer
• liver

• Dlk1
• Fetal liver
• Hematopoietic stem cell
• Hepatic stem cell
• Hepatoblast
• Liver stem cell

• Differentiation
• Dlk1
• Hepatic stem cells
• Isoforms

During prenatal development the liver is composed of multiple cell types with unique properties compared to their adult counterparts. We aimed to establish multilineage cultures of human fetal liver cells that could maintain stem cell and progenitor populations found in the developing liver. An aim of this study was to test if maturation of fetal hepatocytes in short-term cultures supported by epidermal growth factor and oncostatin M can improve their ability to engraft immunodeficient mice. Fetal liver cultures supported a mixture of albumin⁺ cytokertin-19⁺ hepatoblasts, hepatocytes, cholangiocytes, CD14⁺⁺CD32⁺ liver sinusoidal endothelial cells (LSECs) and CD34⁺CD133⁺ haematopoietic stem cells. Transplantation of cultured cells into uPA-NOG or TK-NOG mice yielded long-term engraftment of hepatocytes, abundant LSEC engraftment and multilineage haematopoiesis. Haematopoietic engraftment included reconstitution of B-, T- and NK-lymphocytes. Colonies of polarized human hepatocytes were observed surrounded by human LSECs in contact with human CD45⁺ blood cells in the liver sinusoids. Thus, fetal liver cultures support multiple cell lineages including LSECs and haematopoietic stem cells while also promoting the ability of fetal hepatocytes to engraft adult mouse livers. Fetal liver cultures and liver-humanized mice created from these cultures can provide useful model systems to study liver development, function and disease.

• fetal liver
• haematopoietic stem cells
• hepatocytes
• humanized mice
• liver culture
• sinusoidal endothelium

• CD90
• Gli13
• Janus kinase 2
• Sonic Hegdehog
• liver cancer
• signal transducer and activator of transcription 3
• stem cell

• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Hedgehog Proteins/metabolism
• Humans
• Interleukin-6/metabolism
• Janus Kinase 2/metabolism
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Male
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• STAT3 Transcription Factor/metabolism
• Thy-1 Antigens/genetics
• Thy-1 Antigens/metabolism
• Zinc Finger Protein GLI1/genetics
• Zinc Finger Protein GLI1/metabolism
• Zinc Finger Protein Gli3/genetics
• Zinc Finger Protein Gli3/metabolism

• Gene expression
• Hepatocyte nuclear factor-4
• Liver
• Oncogenesis
• Pathology

Common marmoset (Callithrix jacchus) is emerging as a clinically relevant nonhuman primate model for various diseases, but is hindered by the availability of marmoset cell lines, which are critical for understanding the disease pathogenesis and drug/toxicological screening prior to animal testing. Here we describe the generation of immortalized marmoset hepatic progenitor cells (MHPCs) by lentivirus-mediated transfer of the simian virus 40 large T antigen gene in fetal liver polygonal cells. MHPCs proliferate indefinitely in vitro without chromosomal alteration and telomere shortening. These cells possess hepatic progenitor cell-specific gene expression profiles with potential to differentiate into both hepatocytic and cholangiocytic lineages in vitro and in vivo and also can be genetically modified. Importantly, injected MHPCs repopulated the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice with hepatocyte-like cells. MHPCs also engraft as cholangiocytes into bile ducts of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced bile ductular injured mice. MHPCs provide a tool to enable efficient derivation and genetic modification of both hepatocytes and cholangiocytes for use in disease modeling, tissue engineering, and drug screening.

• Adult liver stem cells
• HL1-hT1
• Liver tumor-promotion
• Microcystin-LR
• Multidrug resistance proteins
• OATP

Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in order to counteract telomere shortening, to preserve telomeres from DNA damage repair systems and to avoid telomere-mediated senescence and/or apoptosis. For this reason, telomere maintenance is an essential step in cancer progression. Most human tumors maintain their telomeres expressing telomerase, whereas a lower but significant proportion activates the alternative lengthening of telomeres (ALT) pathway. However, evidence about the coexistence of ALT and telomerase has been found both in vivo in the same cancer populations and in vitro in engineered cellular models, making the distinction between telomerase- and ALT-positive tumors elusive. Indeed, after the development of drugs able to target telomerase, the capability for some cancer cells to escape death, switching from telomerase to ALT, was highlighted. Unfortunately, to date, the mechanism underlying the possible switching or the coexistence of telomerase and ALT within the same cell or populations is not completely understood and different factors could be involved. In recent years, different studies have tried to shed light on the complex regulation network that controls the transition between the two TMMs, suggesting a role for embryonic cancer origin, epigenetic modifications, and specific genes activation—both in vivo and in vitro. In this review, we examine recent findings about the cancer-associated differential activation of the two known TMMs and the possible factors implicated in this process. Furthermore, some studies on cancers are also described that did not display any TMM.

• alternative lengthening of telomeres (ALT)
• cancer
• cancer therapy
• telomerase
• telomere

• Animals
• Humans
• Neoplasms/metabolism
• Phenotype
• Telomerase/metabolism
• Telomere/metabolism
• Telomere Homeostasis

• Children
• Hepatic metabolic disorder
• Hepatocyte isolation
• Liver cell transplantation
• Liver failure

Introduction: Hepatoblastoma (HB) is the most common primary malignant liver neoplasm in children. Its increasing survival rate is related to the progress in modern imaging, surgical techniques, and new chemotherapy regimens.

Clinical approach: One of the past achievements was the development of the pretreatment extension of disease (PRETEXT) system. Gradually, the HB therapeutic approach has become more individualized with better stratification of patients.

Controversies: These include the need for preoperative chemotherapy and its optimal duration; intensity of preoperative chemotherapy required for locally advanced cases (PRETEXT 4); optimal surgical treatment for locally advanced tumors: aggressive hepatic resections versus liver transplantation; the role of postoperative chemotherapy in the post-transplant setting; the timing and role of metastasectomy in patients with disseminated disease who undergo partial liver resection; and the prognostic significance of several HB pathology variants.

Hepatoblastoma biology: Beta-catenin mutations and the beta-catenin/Wnt pathway play an important role in HB development. There have been at least two molecular signatures in HB published. Unluckily, all of these findings are based on relatively small clinical series and require confirmation.

Conclusion: The treatment of HB started from one and the same therapy for all patients and aimed at increased treatment individualization, but the future seems to lie in biology-driven patient-tailored therapies.

• PRETEXT
• biology
• chemotherapy
• hepatoblastoma
• liver transplantation
• surgical treatment

• CAR-T
• Mesenchymal stem cells
• Stem cell

• CD326
• EpCAM
• hepatocyte
• liver
• progenitor
• stem cell

Oval cells, specific liver progenitors, are activated in response to injury. The human umbilical cord blood (hUCB) is a possible source of transplantable hepatic progenitors and can be used in cases of severe liver injury. We detected the effect of hUCB stem cell transplantation on natural response of oval cells to injury.

Twenty-four female albino rats were randomly divided into three groups: (A) control, (B) liver injury with hepatocyte block, and (C) hUCB transplanted group. Hepatocyte block was performed by administration of 2-acetylaminofluorene (2-AAF) for 12 days. CCL4 was administrated at day 5 from experiment start. Animals were sacrificed at 9 days post CCL4 administration, and samples were collected for biochemical and histopathological analysis. Oval cell response to injury was evaluated by the percentage of oval cells in the liver tissue and frequency of cells incorporated into new ducts.

Immunohistochemical analysis of oval cell response to injury was performed. There was significant deviation in the hUCB-transplanted (4.9 ± 1.4) and liver injury groups (2.4 ± 0.9) as compared to control (0.89 ± 0.4) 9 days post injury. Detection of oval cell response was dependant on OV-6 immunoreactivity. For mere localization of cells with human origin, CD34 antihuman immunoreactivity was performed. There was no significant difference in endogenous OV-6 immunoreactivity following stem cell transplantation as compared to the liver injury group.

In vivo transplantation of cord blood stem cells (hUCB) does not interfere with natural oval cell response to liver injury.

• CD34
• Chronic injury
• Liver
• OV-6
• Oval cells
• hUCB

In the early fetal liver, hematopoietic progenitors expand and mature together with hepatoblasts, the liver progenitors of hepatocytes and cholangiocytes. Previous analyses of human fetal livers indicated that both progenitors support each other's lineage maturation and curiously share some cell surface markers including CD34 and CD133. Using the human embryonic stem cell (hESC) system, we demonstrate that virtually all hESC-derived hepatoblast-like cells (Hep cells) transition through a progenitor stage expressing CD34 and CD133 as well as GATA2, an additional hematopoietic marker that has not previously been associated with human hepatoblast development. Dynamic expression patterns for CD34, CD133, and GATA2 in hepatoblasts were validated in human fetal livers collected from the first and second trimesters of gestation. Knockdown experiments demonstrate that each gene also functions to regulate hepatic fate mostly in a cell-autonomous fashion, revealing unprecedented roles of fetal hematopoietic progenitor markers in human liver progenitors.

•

Co-expression of hematopoietic markers CD34, CD133, and GATA2 in hESC-Hep cells

• hematopoietic progenitor marker
• hepatoblast
• human embryonic stem cell
• human liver development

• Cell transplantation
• Fetal stem cells
• Liver
• Liver regeneration
• Progenitor cells
• Stem cell transplantation

Hypoxia promotes tumor malignancy in solid tumors. One key mechanism by which this occurs is via epigenetic alteration. The present study demonstrates that hypoxia upregulates the expression of the ten-eleven-translocation 5-methylcytosine dioxygenase (TET) enzymes, which catalyze the conversion of 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), thereby leading to elevated cellular 5-hmC levels in hepatoblastoma HepG2 cells. Hypoxia inducible factor-1α (HIF-1α) is the main transcription factor activated by hypoxia. A chemical inducer of HIF-1α, CoCl₂, also increases the expression of TET enzymes. Knockdown of HIF-1α attenuates the hypoxia-induced expression of TET enzymes. These results indicate that hypoxia controls DNA methylation through HIF-1α-mediated TET enzyme regulation in HepG2 cells.

• 5-hydroxymethylcytosine
• hypoxia
• hypoxia inducible factor-1α
• methylation
• ten-eleven-translocation 5-methylcytosine dioxygenase

• fetal stem cells
• hepatoblasts
• liver
• physiological stress
• progenitor cells
• stem cells