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liver repopulation

Amber W Wang, Kirk J Wangensteen, Yue J Wang, Adam M Zahm, Nicholas G Moss, Noam Erez, Klaus H Kaestner
Understanding the molecular basis of the regenerative response following hepatic injury holds promise for improved treatments of liver diseases. Here, we report an innovative method to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury. We utilize the Fah-/- mouse, a model of hereditary tyrosinemia, which conditionally undergoes severe liver injury unless fumarylacetoacetate hydrolase (FAH) expression is reconstituted ectopically. We employ translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs specific to repopulating hepatocytes...
March 8, 2018: Journal of Clinical Investigation
Ran-Ran Zhang, Yun-Wen Zheng, Bin Li, Yun-Zhong Nie, Yasuharu Ueno, Tomonori Tsuchida, Hideki Taniguchi
BACKGROUND: Mature human hepatocytes are critical in preclinical research and therapy for liver disease, but are difficult to manipulate and expand in vitro. Hepatic stem cells (HpSCs) may be an alternative source of functional hepatocytes for cell therapy and disease modeling. Since these cells play an import role in regenerative medicine, the precise characterization that determines specific markers used to isolate these cells as well as whether they contribute to liver regeneration still remain to be shown...
February 5, 2018: Stem Cell Research & Therapy
Sandeep Kumar Vishwakarma, Avinash Bardia, Chandrakala Lakkireddy, Raju Nagarapu, Md Aejaz Habeeb, Aleem Ahmed Khan
AIM: To develop appropriate humanized three-dimensional ex-vivo model system for drug testing. METHODS: Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses...
January 27, 2018: World Journal of Hepatology
Michael Thomaschewski, Kristoffer Riecken, Ludmilla Unrau, Tassilo Volz, Kerstin Cornils, Harald Ittrich, Denise Heim, Henning Wege, Ercan Akgün, Marc Lütgehetmann, Jan Dieckhoff, Michael Köpke, Maura Dandri, Daniel Benten, Boris Fehse
We recently introduced red-green-blue (RGB) marking for clonal cell tracking based on individual color-coding. Here, we applied RGB marking to study clonal development of liver tumors. Immortalized, non-tumorigenic human fetal hepatocytes expressing the human telomerase reverse transcriptase (FH-hTERT) were RGB-marked by simultaneous transduction with lentiviral vectors encoding mCherry, Venus, and Cerulean. Multi-color fluorescence microscopy was used to analyze growth characteristics of RGB-marked FH-hTERT in vitro and in vivo after transplantation into livers of immunodeficient mice with endogenous liver damage (uPA/SCID)...
December 29, 2017: Oncotarget
Daniel Benten, Johannes Kluwe, Jan W Wirth, Nina D Thiele, Antonia Follenzi, Kuldeep K Bhargava, Christopher J Palestro, Michael Koepke, Reni Tjandra, Tassilo Volz, Marc Lutgehetmann, Sanjeev Gupta
Hepatic stellate cells (HSCs) are major contributors to liver fibrosis, as hepatic injuries may cause their transdifferentiation into myofibroblast-like cells capable of producing excessive extracellular matrix proteins. Also, HSCs can modulate engraftment of transplanted hepatocytes and contribute to liver regeneration. Therefore, understanding the biology of human HSCs (hHSCs) is important, but effective methods have not been available to address their fate in vivo. To investigate whether HSCs could engraft and repopulate the liver, we transplanted GFP-transduced immortalized hHSCs into immunodeficient NOD/SCID mice...
January 19, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Min-Jun Wang, Fei Chen, Qing-Gui Liu, Chang-Cheng Liu, Hao Yao, Bing Yu, Hai-Bin Zhang, He-Xin Yan, Yibiao Ye, Tao Chen, Kirk J Wangensteen, Xin Wang, Yi-Ping Hu, Zhi-Ying He
Hepatocyte transplantation holds great promise as an alternative to orthotopic organ transplantation in the treatment of liver diseases. However, obtaining clinically meaningful levels of liver repopulation has not been achieved because the mechanisms regulating hepatocyte proliferation in recipient livers have not yet been well characterized. In the mouse model of Hereditary Tyrosinemia Type I, the fumarylacetoacetate hydrolase-deficient (Fah-/-) mouse, we found gradually increasing expression level of insulin-like growth factor 2 (IGF2) in the hepatocytes of host livers...
January 18, 2018: Cell Death & Disease
Sangeetha Satheesan, Haitang Li, John C Burnett, Mayumi Takahashi, Shasha Li, Shiny Xiaqin Wu, Timothy W Synold, John J Rossi, Jiehua Zhou
Although current combinatorial antiretroviral therapy (cART) is therapeutically effective in the majority of HIV patients, interruption of therapy can cause a rapid rebound in viremia, demonstrating the existence of a stable reservoir of latently infected cells. HIV latency is therefore considered a primary barrier to HIV eradication. Identifying, quantifying, and purging the HIV reservoir is crucial to effectively curing patients and relieving them from the lifelong requirement for therapy. Latently infected transformed cell models have been used to investigate HIV latency; however, they cannot accurately represent the quiescent cellular environment of primary latently infected cells in vivo...
January 17, 2018: Journal of Virology
Ta-Lun Kao, Yao-Li Chen, Yu-Ping Kuan, Wei-Chun Chang, Yu-Chen Ho, Shuyuan Yeh, Long-Bin Jeng, Wen-Lung Ma
BACKGROUND: After living donor liver transplantation (LDLT), rising serum bilirubin levels commonly indicate insufficient numbers of hepatocytes are available to metabolize bilirubin into biliverdin. Recovery of bilirubin levels is an important marker of hepatocyte repopulation after LDLT. Cytochrome P450 (CYP) 2A6 in humans (or cyp2a4 in rodents) can function as "bilirubin oxidase." Functional hepatocytes contain abundant CYP2A6, which is considered a marker for hepatocyte function recovery...
November 2017: Cell Transplantation
Apeksha Damania, Anupam Kumar, Arun K Teotia, Haruna Kimura, Masamichi Kamihira, Hiroyuki Ijima, Shiv Kumar Sarin, Ashok Kumar
Recent progress in the use of decellularized organ scaffolds as regenerative matrices for tissue engineering holds great promise in addressing the issue of donor organ shortage. Decellularization preserves the mechanical integrity, composition, and microvasculature critical for zonation of hepatocytes in the liver. Earlier studies have reported the possibility of repopulating decellularized matrices with hepatic cell lines or stem cells to improve liver regeneration. In this work, we study the versatility of the decellularized liver matrix as a substrate coating of three-dimensional cryogel scaffolds...
January 10, 2018: ACS Applied Materials & Interfaces
Ogechi Ogoke, Janet Oluwole, Natesh Parashurama
Background: Liver disease contributes significantly to global disease burden and is associated with rising incidence and escalating costs. It is likely that innovative approaches, arising from the emerging field of liver regenerative medicine, will counter these trends. Main body: Liver regenerative medicine is a rapidly expanding field based on a rich history of basic investigations into the nature of liver structure, physiology, development, regeneration, and function...
2017: Journal of Biological Engineering
Salamah M Alwahsh, Hassan Rashidi, David C Hay
The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought...
November 27, 2017: Cellular and Molecular Life Sciences: CMLS
Kirk J Wangensteen, Yue J Wang, Zhixun Dou, Amber W Wang, Elham Mosleh-Shirazi, Max A Horlbeck, Luke A Gilbert, Jonathan S Weissman, Shelley L Berger, Klaus H Kaestner
CRISPR/Cas9 activation (CRISPRa) systems have enabled genetic screens in cultured cells lines to discover and characterize drivers and inhibitors of cancer cell growth. We adapted this system for use in vivo to assess whether modulating endogenous gene expression levels can result in functional outcomes in the native environment of the liver. We engineered the dCas9(+) mouse, a Cre-inducible CRISPRa system for cell type-specific gene activation in vivo. We tested the capacity for genetic screening in live animals by applying CRISPRa in a clinically relevant model of liver injury and repopulation...
November 1, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Masashi Uchida, Yoriko Tajima, Masakazu Kakuni, Yutaka Kageyama, Taro Okada, Eri Sakurada, Chise Tateno, Ryoji Hayashi
The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and DDIs via transporters may be a risk factor for adverse events. Cyclosporine A, a strong OATP inhibitor, has been reported to increase the systemic exposure of rosuvastatin, an OATP substrate, by 7.1-fold in clinical studies. PXB mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes and have been widely used for drug discovery in drug metabolism and pharmacokinetics studies...
January 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Florie Borel, Qiushi Tang, Gwladys Gernoux, Cynthia Greer, Ziqiong Wang, Adi Barzel, Mark A Kay, Leonard D Shultz, Dale L Greiner, Terence R Flotte, Michael A Brehm, Christian Mueller
Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In α-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver...
November 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
Wessam Hassanein, Arielle Cimeno, Avraham Werdesheim, Bryan Buckingham, Joshua Harrison, Mehmet C Uluer, Ali Khalifeh, Carlos Rivera-Pratt, Stephen Klepfer, Jhade D Woodall, Urmil Dhru, Elliot Bromberg, Dawn Parsell, Cinthia Drachenberg, Rolf N Barth, John C LaMattina
Organ scaffold bioengineering is currently limited by the inability to effectively repopulate the scaffold with appropriately distributed functional cells. We examined the feasibility of a decellularized liver scaffold to support the growth and function of multilineage allogenic cells derived from either adult or neonatal liver cells. Cell slurries from neonatal and adult rat livers containing hepatocytes, cholangiocytes, and endothelial cells were introduced into decellularized adult rat liver scaffolds via the bile duct...
November 30, 2017: Tissue Engineering. Part A
Ping Wang, Min Cong, Tianhui Liu, Hufeng Xu, Lin Wang, Guangyong Sun, Aiting Yang, Dong Zhang, Jian Huang, Yameng Sun, Wenshan Zhao, Hong Ma, Jidong Jia, Hong You
BACKGROUND: Although they are expandable in vitro, hepatic progenitors are immature cells and share many immunomarkers with hepatocellular carcinoma, raising potential concerns regarding maltransformation after transplantation. This study investigated the effects of hepatic nuclear factor (HNF) 4α on the proliferation, migration, and maltransformation of hepatic progenitors and determined the feasibility of using these manipulated cells for transplantation. METHODS: The effects of HNF4α on rat hepatic progenitors (i...
August 14, 2017: Stem Cell Research & Therapy
Markus Grompe
Several animal models of Fah deficiency have been developed, including mice, pigs and most recently rats. Initially, the murine models were developed with the intent to mirror the human disease for pathophysiologic and therapeutic studies. However, it soon became apparent that Fah-positive hepatocytes have a potent selective growth advantage in mutant liver and can extensively repopulate the diseased organ. For this reason, Fah mutant mice have become a workhorse for liver biology and are widely used in liver stem cell and hepatic gene therapy research...
2017: Advances in Experimental Medicine and Biology
Joan M Boylan, Heather Francois-Vaughan, Philip A Gruppuso, Jennifer A Sanders
BACKGROUND: The limited availability of donor organs has led to a search for alternatives to liver transplantation to restore liver function and bridge patients to transplantation. We have shown that the proliferation of late gestation (embryonic day 19) fetal rat hepatocytes is mitogen-independent and that mechanisms regulating mRNA translation, cell cycle progression, and gene expression differ from those of adult rat hepatocytes. In the present study, we investigated whether E19 fetal hepatocytes can engraft and repopulate an injured adult liver...
October 2017: Transplantation
Etienne M Sokal, Catherine Anne Lombard, Véronique Roelants, Mustapha Najimi, Sharat Varma, Camillo Sargiacomo, Joachim Ravau, Giuseppe Mazza, François Jamar, Julia Versavau, Vanessa Jacobs, Marc Jacquemin, Stéphane Eeckhoudt, Catherine Lambert, Xavier Stéphenne, Françoise Smets, Cédric Hermans
BACKGROUND: With the exception of liver transplantation, there is no cure for hemophilia, which is currently managed by preemptive replacement therapy. Liver-derived stem cells are in clinical development for inborn and acquired liver diseases and could represent a curative treatment for hemophilia A. The liver is a major factor VIII (FVIII) synthesis site, and mesenchymal stem cells have been shown to control joint bleeding in animal models of hemophilia. Adult-derived human liver stem cells (ADHLSCs) have mesenchymal characteristics and have been shown able to engraft in and repopulate both animal and human livers...
August 2017: Transplantation
Yibin Chen, Sharon Geerts, Maria Jaramillo, Basak E Uygun
Severe liver disease is the 12th leading cause of death in the USA, with organ transplantation often being the only viable option for treatment. However, due to the shortage of viable donor livers, it is estimated that over 1200 patients died in 2015 while waiting for liver transplantation. This highlights the need for alternative sources of viable organs. In this study, we describe a method that provides the groundwork for the development of functional liver grafts. The approach described here is for removal of cells from intact livers and subsequently repopulating them with functional liver cells...
July 23, 2017: Methods in Molecular Biology
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