Silvia Liu's research while affiliated with University of Pittsburgh and other places
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Publications (88)
Background
The liver is the only organ with the ability to regenerate following surgical or toxicant insults, and partial hepatectomy serves as an experimental model of liver regeneration (LR). Dynamic changes in gene expression occur from the periportal to pericentral regions of the liver following partial hepatectomy; thus, spatial transcriptomic...
Obesity is increasing worldwide and leads to a multitude of metabolic diseases, including cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis (NASH). Cysteine-rich angiogenic inducer 61 (CYR61) is associated with the progression of NASH, but it has been described to have anti- and proinflammat...
Calponin 2 (CNN2) is a prominent actin stabilizer. It regulates fatty acid oxidation (FAO) by interacting with estrogen receptor 2 (ESR2) to determine kidney fibrosis. However, whether CNN2 is actively involved in acute kidney injury (AKI) remains unclear. Here, we report that CNN2 was induced in human and animal kidneys after AKI. Knockdown of CNN...
Background:
We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPK...
Background & aims:
β-catenin, the effector molecule of the Wnt signaling pathway, has been shown to play a crucial role in bile acid homeostasis through direct inhibition of farnesoid X receptor (FXR), which has pleiotropic effects on bile acid homeostasis. We hypothesize that simultaneous suppression of β-catenin signaling and activation of FXR i...
We studied osteoblast bone mineral transport and matrix proteins as a function of age. In isolated bone marrow cells from long bones of young (3-4 month) and old (18-19 month) mice, age correlated with reduced mRNA of mineral transport proteins: alkaline phosphatase (ALP), ankylosis (ANK), the Cl-/H+ exchanger ClC3, and matrix proteins collagen 1 (...
The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Protein mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthe...
The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Protein mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthe...
Expression of TMEM16A, a calcium activated chloride channel, is elevated in some human cancers and impacts tumor cell proliferation, metastasis and patient outcome. Evidence presented here uncovers a molecular synergy between TMEM16A and mTOR, a serine-threonine kinase that is known to promote cell survival and proliferation in cholangiocarcinoma (...
Background
In idiopathic pulmonary fibrosis (IPF) myofibroblasts are key effectors of fibrosis and architectural distortion by excessive deposition of extracellular matrix and their acquired contractile capacity. Single-cell RNA-sequencing (scRNA-seq) has precisely defined the IPF myofibroblast transcriptome, but identifying critical transcription...
The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Protein mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthe...
Background & aims:
Vinyl chloride (VC) monomer is a volatile organic compound commonly used in industry. At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.e., sub-regulatory exposure limits) that do not directly damage the liver, enhance injury caused by Western diet (WD). It...
The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Protein mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthe...
Introduction
Thromboinflammatory complications are well described sequalae of Coronavirus Disease 2019 (COVID-19), and there is evidence of both hyperreactive platelet and inflammatory neutrophil biology that contributes to the thromoinflammatory milieu. It has been demonstrated in other thromboinflammatory diseases that the circulating environment...
Objective:
In the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy. However, how cellular mechanics and metabolism are connected remains unclear.
Methods:
A multi-disciplinary approach was employed: the fibrotic kidney disease models wer...
Hepatic zonation is critical for most metabolic functions in liver. Wnt signaling plays an important role in establishing and maintaining liver zonation. Yet, the anatomic expression of Wnt signaling components, especially all 10 Frizzled receptors (Fzds), has not been characterized in adult liver. To address this, we quantitatively mapped the spat...
Prostate cancer remains one of the most lethal malignancies for men in the United States. Predicting the course of prostate cancer is challenging since only a fraction of prostate cancer patients experienced cancer recurrence after radical prostatectomy or radiation therapy. In this report, the expressions of 14 fusion genes in 607 prostate cancer...
In osteoarthritis (OA), chondrocytes undergo many pathological alternations that are linked with cellular senescence. However, the exact pathways that lead to the generation of a senescence‐like phenotype in OA chondrocytes are not clear. Previously, we found that loss of estrogen receptor‐α (ERα) was associated with an increased senescence level i...
In the fibrotic kidneys, the extent of a formed deleterious microenvironment is determined by cellular mechanical forces. This process requires metabolism for energy; however, how cellular mechanics and metabolism are connected remains unclear. Our proteomics revealed that actin filament binding and cell metabolism are the two most dysregulated eve...
Background
Human multipotent progenitor cells (hiMPCs) created from induced pluripotent stem cells (iPSCs) represent a new cell source for cartilage regeneration. In most studies, bone morphogenetic proteins (BMPs) are needed to enhance transforming growth factor-β (TGFβ)-induced hiMPC chondrogenesis. In contrast, TGFβ alone is sufficient to result...
While rare compared to adult liver cancers, hepatoblastoma is the most common pediatric liver malignancy and its incidence is increasing. Treatment currently includes surgical resection with or without chemotherapy but in severe cases children require liver transplantation. The effort to develop more target, hepatoblastoma specific therapies have b...
The conclusive identity of Wnts regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of β-catenin. Using single-cell analysis, we identified a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3. EC-elimination of Wnt2 and Wnt9b led to both loss of β-catenin targets in zone 3, and re-a...
Hepatic zonation is critical for most metabolic functions in liver. Wnt signaling plays an important role in establishing and maintaining liver zonation. Yet, the anatomic expression of Wnt signaling components, including all 10 Frizzled receptors (Fzds), has not been characterized in adult liver. To address this, we quantitatively mapped the spati...
Human Mesenchymal Stem Cell‐Derived Miniature Joint System In article number 2105909 by Rocky S. Tuan, Hang Lin, and co‐workers, a miniature synovial joint‐mimicking system (miniJoint) is established in a microfluidics‐enabled bioreactor, in which human mesenchymal stem cell‐derived bone‐cartilage complex, synovial‐like fibrous tissue, and adipose...
Prediction of the clinical outcomes of prostate cancer remains a challenge. Recently, we discovered a panel of 8 fusion genes that occurred in aggressive prostate cancer. In order to make the fusion gene test clinically ready as a predictor, we have modified to test into a semi-quantitative Taqman QRT-PCR. In the funding period, Two hundred seventy...
Prediction of the clinical outcomes of prostate cancer remains a challenge. Recently, we discovered a panel of 8 fusion genes that occurred in aggressive prostate cancer. In order to make the fusion gene test clinically ready as a predictor, we have modified to test into a semi-quantitative Taqman QRT-PCR. In the funding period, Two hundred seventy...
Introduction:
Intrahepatic cholangiocarcinoma (iCCA) is a liver tumor of increasing incidence and devastating prognosis. The most critical barrier for developing a globally effective therapy for iCCA is molecular heterogeneity caused by diverse molecular drivers and cellular origins in the liver. Clinically, over 90% of iCCAs show alterations of Y...
Introduction:
Hepatoblastoma (HB) is the most common pediatric liver malignancy. While relatively rare, its incidence is increasing. Currently surgical resection with or without chemotherapy is the main treatment for the tumor though in severe cases children require liver transplantation. Development of precision therapy for the tumor has been ham...
We previously demonstrated that loss of Yes‐associated protein 1 (YAP1) in early liver development (YAP1 KO) leads to an Alagille syndrome‐like phenotype with absence of intrahepatic bile ducts and severe cholestasis accompanied by chronic hepatocyte adaptations to reduce liver injury. We noticed that TAZ, a paralog of YAP1, was significantly upreg...
Background and Aim
Intrahepatic cholangiocarcinoma (ICC) is a devastating liver cancer with extremely high intra- and inter-tumoral molecular heterogeneity, partly due to its diverse cellular origins. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development.
Methods
Expression of ICC driver...
Diseases of the knee joint such as osteoarthritis (OA) affect all joint elements. An in vitro human cell‐derived microphysiologica system capable of simulating intraarticular tissue crosstalk is desirable for studying etiologies/pathogenesis of joint diseases and testing potential therapeutics. Herein, a human mesenchymal stem cell‐derived miniatur...
The conclusive identity of Wnt proteins regulating liver zonation (LZ) and regeneration (LR) remains unclear despite an undisputed role of b-catenin. Using single-cell analysis of liver cells from various species, a conserved Wnt2 and Wnt9b expression in endothelial cells (ECs) in zone 3 shown to be the major Wnt cell source, was identified. Condit...
Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in children. The mechanisms that drive NAFLD disease progression in this specific patient population remain poorly defined. In this study, we obtained liver biopsy samples from a multiethnic cohort of pediatric patients with NAFLD (n = 52, mean age = 13.6 year...
Background & Aims
Vinyl chloride (VC) monomer is a volatile organic compound commonly used in industry to produce polyvinyl chloride (PVC). At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.e., < regulatory exposure limits) that do not directly damage the liver, enhance injury...
Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts. We have previously demonstrated the importance of Wnt/β-catenin signaling in mouse models of PSC. In this study, we wished to determine the clinical relevance of β-catenin localization in patie...
Objective
In knee cartilage from patients with osteoarthritis (OA), both preserved cartilage and damaged cartilage are observed. In this study, we aim to compare preserved with damaged cartilage to identify the molecule(s) that may be responsible for the mechanical loading-induced differences within cartilage degradation.
Methods
Preserved and dam...
Objectives
Diabetic kidney disease (DKD) is the most common microvascular complication of type 2 diabetes mellitus (2-DM). Currently, urine and kidney biopsy specimens are the major clinical resources for DKD diagnosis. Our study proposes to evaluate the diagnostic value of blood in monitoring the onset of DKD and distinguishing its status in the c...
Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. Liver transplantation has been an effective approach to treat liver cancer. However, significant numbers of patients with HCC experience cancer recurrence, and the selection of suitable candidates for liver transplant remains a challenge. We developed a model to predict the lik...
Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of b-catenin, one with b-catenin loss is hepatocytes and BE...
Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic knockouts of β-catenin, one with ß-catenin loss is hepatocytes and BECs (KO...
Chromosome rearrangement is one of the hallmarks of human malignancies. Gene fusion is one of the consequences of chromosome rearrangements. In this report, we show that gene fusion between solute carrier family 45 member 2 (SLC45A2) and alpha‐methylacyl‐coenzyme A racemase (AMACR) occurs in eight different types of human malignancies, with frequen...
The kidney local microenvironment (KLM) plays a critical role in the pathogenesis of kidney fibrosis. However, the composition and regulation of a fibrotic KLM remain unclear. Through a multidisciplinary approach, we investigated the roles of the hepatocyte growth factor /c-met signaling pathway in regulating KLM formation in various chronic kidney...
Prostate cancer remains one of the most lethal cancers for men in the United States. The study aims to detect fusion transcripts in the blood samples of prostate cancer patients. We analyzed nine fusion transcripts including MAN2A1-FER, SLC45A2-AMACR, TRMT11-GRIK2, CCNH-C5orf30, mTOR-TP53BP1, KDM4-AC011523.2, TMEM135-CCDC67, LRRC59-FLJ60017 and Pte...
We previously identified an up-regulation of specific Wnt proteins in the cholangiocyte compartment during cholestatic liver injury and found that mice lacking Wnt secretion from hepatocytes and cholangiocytes showed fewer proliferating cholangiocytes and high mortality in response to a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet, a murine...
Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis (OA). In this study, we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs (DMOADs). Specifically, human bone marrow-derived mesenchymal stromal cells (MSCs) were expanded in vitro up to pass...
The characterization of human gene expression is limited by short read lengths, high error rates and large input requirements. Here, we used a synthetic long read (SLR) sequencing approach, LoopSeq, to generate accurate sequencing reads that span full length transcripts using standard short read data. LoopSeq identified isoforms from control sample...
Hepatocytes are highly polarized epithelia. Loss of hepatocyte polarity is associated with various liver diseases, including cholestasis. However, the molecular underpinnings of hepatocyte polarization remain poorly understood. Previously, we have shown that loss of β-catenin at adherens junctions (AJs) is compensated by γ-catenin and dual loss of...
Objective: Necrotizing enterocolitis (NEC) is characterized by peripheral cell abnormalities, yet few studies have analyzed the complete blood count (CBC) specifically by gestational age (GA). Our objective was to describe GA-specific immune abnormalities in NEC through a comprehensive analysis of the CBC differential.
Methods: Using a cohort of 24...
Inactivation of Pten gene through deletions and mutations leading to excessive pro-growth signaling pathway activations frequently occurs in cancers. Here, we report a Pten derived pro-cancer growth gene fusion Pten-NOLC1 originated from a chr10 genome rearrangement and identified through a transcriptome sequencing analysis of human cancers. Pten-N...
Background:
Hepatocellular cancer (HCC) remains a major unmet clinical need. Although activating CTNNB1 mutations are seen in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Co-expression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between β-...
Intrahepatic cholangiocarcinoma (ICC), a disease of poor prognosis, has increased in incidence. It is challenging to treat due to intra- and inter-tumoral heterogeneity, which in part is attributed to diverse cellular origin. Indeed, co-expression of AKT and NICD in hepatocytes (HCs) yielded ICC, with similarity to proliferative, Notch-activated, a...
Diversity in human gene expression stems, to a large extent, from splicing exons into multiple mRNA isoforms. Characterization of isoforms requires accurate long-read sequencing. However, read lengths, high error rates, low throughput and large input requirements are some of the challenges that remain to be addressed in sequencing technologies.
In...
Background & Aims
The heterodimeric integrin receptor α4β7 regulates CD4 T cell recruitment to inflamed tissues, but its role in the pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. Here we examined the role of α4β7-mediated recruitment of CD4 T cells to the intestine and liver in NASH.
Methods
Male littermate F11r+/+ (control) and...
Background:
Studies have suggested that estrogens may protect mice from AKI. Estrogen sulfotransferase (SULT1E1, or EST) plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens, but studies on the role of SULT1E1 in AKI are lacking.
Methods:
We used the renal ischemia-reperfusion model to investigate the role of...
We have previously shown that co‐expression of hMet and mutant‐β‐catenin (S33Y or S45Y) using sleeping beauty transposon/transposase via hydrodynamic tail vein injection (SB‐HTVI) leads to HCC in mice referred to as Met‐b‐catenin model, which represented 11% of human HCC. Since Met signaling can activate downstream signaling including Ras, AKT/PI3K...
The most critical barrier for developing a globally effective regimen for Intrahepatic cholangiocarcinoma (ICC) is its intra‐ and extratumoral heterogeneity, which may be partly due to diverse cellular origin within the liver. Recent studies have suggested hepatocytes (HCs) as a cell source in a subset of ICCs, especially those associated with chro...
Background
Hepatocellular cancer (HCC) remains a major clinical need with gradually increasing incidence and currently lacks precision therapy. Thus, there is a need to better characterize molecular drivers in HCC and generate relevant models to test biology and therapies. In the USA, CTNNB1 mutations occur in 26% of all HCCs, however they alone ar...
The progress in the field of high-dimensional cytometry has greatly increased the number of markers that can be simultaneously analyzed producing datasets with large numbers of parameters. Traditional biaxial manual gating might not be optimal for such datasets. To overcome this, a large number of automated tools have been developed to aid with cel...
Background and aims:
Hepatic crisis is an emergent complication affecting patients with sickle cell disease (SCD); however, the molecular mechanism of sickle cell hepatobiliary injury remains poorly understood. Using the knock-in humanized mouse model of SCD and SCD patient blood, we sought to mechanistically characterize SCD-associated hepato-pat...
Chronic cholestasis results from bile secretory defects or impaired bile flow with few effective medical therapies available. Thyroid hormone triiodothyronine and synthetic thyroid hormone receptor agonists, such as GC-1, are known to impact lipid and bile acid (BA) metabolism and induce hepatocyte proliferation downstream of Wnt/β-catenin signalin...
Age-dependent alterations in microglia behavior have been implicated in neurodegeneration and CNS injuries. Here, we compared the transcriptional profiles of young versus aged microglia during stroke recovery. CD45intermediateCD11b⁺ microglia were FACS-isolated from the brains of young (10-week-old) and aged (18-month-old) male mice with sham opera...
Background:
Globally, diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. As the most common microvascular complication of diabetes, DKD is a thorny, clinical problem in terms of its diagnosis and management. Intensive glucose control in DKD could slow down but not significantly halt disease progression. Revisiting the t...
Hepatocellular carcinoma is one of the most lethal cancers in the United States. Early detection of the disease is crucial for reducing the mortality of this malignancy. Recently, we identified a panel of fusion genes present in several types of human cancers, including hepatocellular carcinoma. Among 8 fusion genes, MAN2A1-FER, TRMT11-GRIK2 and CC...
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related deaths worldwide. While several tyrosine kinase inhibitors (TKIs) have been approved as first or second line therapy for HCC, the overall efficacy of these agents is limited. Thus, developing useful animal models may shed light on the biology of HCC tumor and provide a pl...
Nrf/Keap signaling and Wnt/b‐catenin signaling are important in liver pathophysiology. Mutations in NFE2L2 (encoding for Nrf2) and CTNNB1 (encoding for beta‐catenin) can co‐occur in a subset of HCC patients. However, the precise relevance of these co‐occurrences remains obscure. In the current study, we explored the relevance of any cross‐talk betw...
Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat...
The rapid advances of omics technologies have generated abundant genomic data in public repositories and effective analytical approaches are critical to fully decipher biological knowledge inside these data. Meta-analysis combines multiple studies of a related hypothesis to improve statistical power, accuracy and reproducibility beyond individual s...
Background: The majority of ovarian cancers (OvCa) are exquisitely sensitive to primary cytoreductive surgery and platinum-based agents, yet up to 80% of late-stage disease will relapse and develop deadly resistance to subsequent therapies. Identifying molecular mediators driving this acquired resistance is essential to improve the tragic 12- to 18...
MET and epidermal growth factor receptor (EGFR) tyrosine kinases are crucial for liver regeneration and normal hepatocyte function. Recently we demonstrated that in mice, combined inhibition of these two signaling pathways abolished liver regeneration following hepatectomy, with subsequent hepatic failure and death at 15 to 18 days post-resection....
Miniature chromosome maintenance (MCM) proteins play critical roles in DNA replication licensing, initiation and elongation. MCM8, one of the MCM proteins playing a critical role in DNA repairing and recombination, was found to have overexpression and increased DNA copy number in a variety of human malignancies. The gain of MCM8 is associated with...
Specifically targeting genomic rearrangements and mutations in tumor cells remains an elusive goal in cancer therapy. Here, we used Cas9-based genome editing to introduce the gene encoding the prodrug-converting enzyme herpes simplex virus type 1 thymidine kinase (HSV1-tk) into the genomes of cancer cells carrying unique sequences resulting from ge...
Motivation:
Although coexpression analysis via pair-wise expression correlation is popularly used to elucidate gene-gene interactions at the whole-genome scale, many complicated multi-gene regulations require more advanced detection methods. Liquid association is a powerful tool to detect the dynamic correlation of two gene variables depending on...
Background & aims:
Human tumors and liver cancer cell lines express the product of a fusion between the first 13 exons in the mannosidase α class 2A member 1 gene (MAN2A1) and the last 6 exons in the FER tyrosine kinase gene (FER), called MAN2A1-FER. We investigated whether MAN2A1-FER is expressed by human liver tumors and its role in liver carcin...
Conclusion:
MET and EGFR separately control many nonoverlapping signaling endpoints, allowing for compensation when only one of the signals is blocked, though the combined elimination of the signals is not tolerated; the results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to...