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liver repopulation

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https://www.readbyqxmd.com/read/29352225/a-humanized-mouse-model-of-liver-fibrosis-following-expansion-of-transplanted-hepatic-stellate-cells
#1
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
https://www.readbyqxmd.com/read/29348399/insulin-like-growth-factor-2-is-a-key-mitogen-driving-liver-repopulation-in-mice
#2
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
https://www.readbyqxmd.com/read/29343582/hiv-replication-and-latency-in-a-humanized-nsg-mouse-model-during-suppressive-oral-combinational-art
#3
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
https://www.readbyqxmd.com/read/29338386/estrogen-estrogen-receptor-%C3%AE-signaling-facilitates-bilirubin-metabolism-in-regenerating-liver-through-regulating-cytochrome-p450-2a6-expression
#4
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
https://www.readbyqxmd.com/read/29210278/decellularized-liver-matrix-modified-cryogel-scaffolds-as-potential-hepatocyte-carriers-in-bioartificial-liver-support-systems-and-implantable-liver-constructs
#5
Apeksha Damania, Anupam Kumar, Arun Kumar Teotia, Kimura Haruna, 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 decellularized liver matrix as a substrate coating of 3D cryogel scaffolds...
December 6, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29204185/bioengineering-considerations-in-liver-regenerative-medicine
#6
REVIEW
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
https://www.readbyqxmd.com/read/29181772/liver-cell-therapy-is-this-the-end-of-the-beginning
#7
REVIEW
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
https://www.readbyqxmd.com/read/29091290/combinatorial-genetics-in-liver-repopulation-and-carcinogenesis-with-a-novel-in-vivo-crispr-activation-platform
#8
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
https://www.readbyqxmd.com/read/29051147/organic-anion-transporting-polypeptides-oatps-mediated-drug-drug-interaction-study-between-rosuvastatin-and-cyclosporine-a-in-chimeric-mice-with-humanized-liver
#9
Masashi Uchida, Yoriko Tajima, Masakazu Kakuni, Yutaka Kageyama, Taro Okada, Eri Sakudara, 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 DMPK studies. In the present study, we examined in vivo and in vitro DDIs between rosuvastatin and cyclosporine A in PXB-mice and fresh human hepatocytes (PXB-cells) obtained from PXB-mice...
October 19, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29032169/survival-advantage-of-both-human-hepatocyte-xenografts-and-genome-edited-hepatocytes-for-treatment-of-%C3%AE-1-antitrypsin-deficiency
#10
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
https://www.readbyqxmd.com/read/29017397/liver-scaffolds-support-survival-and-metabolic-function-of-multilineage-neonatal-allogenic-cells
#11
Wessam Hassanein, Arielle Cimeno, Avraham Werdesheim, Bryan Buckingham, Joshua Harrison, Mehmet C Uluer, Ali Khalifeh, Carlos Rivera-Pratts, 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...
October 10, 2017: Tissue Engineering. Part A
https://www.readbyqxmd.com/read/28807057/inhibitory-effects-of-hnf4%C3%AE-on-migration-maltransformation-of-hepatic-progenitors-hnf4%C3%AE-overexpressing-hepatic-progenitors-for-liver-repopulation
#12
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
https://www.readbyqxmd.com/read/28755199/fah-knockout-animals-as-models-for-therapeutic-liver-repopulation
#13
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
https://www.readbyqxmd.com/read/28749819/engraftment-and-repopulation-potential-of-late-gestation-fetal-rat-hepatocytes
#14
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
https://www.readbyqxmd.com/read/28738402/biodistribution-of-liver-derived-mesenchymal-stem-cells-after-peripheral-injection-in-a-hemophilia-a-patient
#15
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
https://www.readbyqxmd.com/read/28735385/preparation-of-decellularized-liver-scaffolds-and-recellularized-liver-grafts
#16
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
https://www.readbyqxmd.com/read/28717194/rapid-production-of-human-liver-scaffolds-for-functional-tissue-engineering-by-high-shear-stress-oscillation-decellularization
#17
Giuseppe Mazza, Walid Al-Akkad, Andrea Telese, Lisa Longato, Luca Urbani, Benjamin Robinson, Andrew Hall, Kenny Kong, Luca Frenguelli, Giusi Marrone, Oliver Willacy, Mohsen Shaeri, Alan Burns, Massimo Malago, Janet Gilbertson, Nigel Rendell, Kevin Moore, David Hughes, Ioan Notingher, Gavin Jell, Armando Del Rio Hernandez, Paolo De Coppi, Krista Rombouts, Massimo Pinzani
The development of human liver scaffolds retaining their 3-dimensional structure and extra-cellular matrix (ECM) composition is essential for the advancement of liver tissue engineering. We report the design and validation of a new methodology for the rapid and accurate production of human acellular liver tissue cubes (ALTCs) using normal liver tissue unsuitable for transplantation. The application of high shear stress is a key methodological determinant accelerating the process of tissue decellularization while maintaining ECM protein composition, 3D-architecture and physico-chemical properties of the native tissue...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28694332/the-ets2-repressor-factor-erf-is-required-for-effective-primitive-and-definitive-hematopoiesis
#18
Ioanna Peraki, James Palis, George Mavrothalassitis
Erf is a gene for a ubiquitously expressed Ets DNA-binding domain-containing transcriptional repressor. Erf haploinsufficiency causes craniosynostosis in humans and mice, while its absence in mice leads to failed chorioallantoic fusion and death at embryonic day 10.5 (E10.5). In this study, we show that Erf is required in all three waves of embryonic hematopoiesis. Mice lacking Erf in the embryo proper exhibited severe anemia and died around embryonic day 14.5. Erf epiblast-specific knockout embryos had reduced numbers of circulating blood cells from E9...
October 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28659616/a-novel-humanized-mouse-lacking-murine-p450-oxidoreductase-for-studying-human-drug-metabolism
#19
Mercedes Barzi, Francis P Pankowicz, Barry Zorman, Xing Liu, Xavier Legras, Diane Yang, Malgorzata Borowiak, Beatrice Bissig-Choisat, Pavel Sumazin, Feng Li, Karl-Dimiter Bissig
Only one out of 10 drugs in development passes clinical trials. Many fail because experimental animal models poorly predict human xenobiotic metabolism. Human liver chimeric mice are a step forward in this regard, as the human hepatocytes in chimeric livers generate human metabolites, but the remaining murine hepatocytes contain an expanded set of P450 cytochromes that form the major class of drug-metabolizing enzymes. We therefore generated a conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene combined with Il2rg (- /-) /Rag2 (- /-) /Fah (- /-) (PIRF) mice...
June 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28535778/exosomes-from-mesenchymal-stem-cells-induce-the-conversion-of-hepatocytes-into-progenitor-oval-cells
#20
Hao-Hsiang Wu, Oscar K Lee
BACKGROUND: We previously reported that mesenchymal stem cells (MSCs) possess therapeutic effects in a murine model of carbon tetrachloride-induced acute liver failure. In the study, we observed that the majority of repopulated hepatocytes were of recipient origin and were adjacent to transplanted MSCs; only a low percentage of repopulated hepatocytes were from transplanted MSCs. The findings indicate that MSCs guided the formation of new hepatocytes. Exosomes are important messengers for paracrine signaling delivery...
May 23, 2017: Stem Cell Research & Therapy
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