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liver repopulation

Satoshi Ogiso, Kentaro Yasuchika, Ken Fukumitsu, Takamichi Ishii, Hidenobu Kojima, Yuya Miyauchi, Ryoya Yamaoka, Junji Komori, Hokahiro Katayama, Takayuki Kawai, Elena Yukie Yoshitoshi, Sadahiko Kita, Katsutaro Yasuda, Shinji Uemoto
A whole-organ regeneration approach, using a decellularised xenogeneic liver as a scaffold for the construction of a transplantable liver was recently reported. Deriving suitable scaffolds was the first step towards clinical application; however, effective recellularisation remains to be achieved. This report presents a strategy for the improvement of the recellularisation process, using novel cell-seeding technique and cell source. We evaluated recellularised liver grafts repopulated through the portal vein or the biliary duct with mice adult hepatocytes or E14...
October 21, 2016: Scientific Reports
Stacey S Huppert, Kathleen M Campbell
PURPOSE OF REVIEW: Although the liver possesses a unique, innate ability to regenerate through mass compensation, transplantation remains the only therapy when damage outpaces regeneration, or liver metabolic capacity is irreversibly impacted. Recent insight from developmental biology has greatly influenced the advancement of alternative options to transplantation in these settings. RECENT FINDINGS: Factors known to direct liver cell specification, expansion, and differentiation have been used to generate hepatocyte-like cells from stem and somatic cells for developing cell therapies...
October 15, 2016: Current Opinion in Organ Transplantation
Ran-Ran Zhang, Yun-Wen Zheng, Hideki Taniguchi
A novel animal model involving chimeric mice with humanized livers established via human hepatocyte transplantation has been developed. These mice, in which the liver has been repopulated with functional human hepatocytes, could serve as a useful tool for investigating human hepatic cell biology, drug metabolism, and other preclinical applications. One of the key factors required for successful transplantation of human hepatocytes into mice is the elimination of the endogenous hepatocytes to prevent competition with the human cells and provide a suitable space and microenvironment for promoting human donor cell expansion and differentiation...
2016: Journal of Visualized Experiments: JoVE
Maja Milanovic, Nicole Heise, Nilushi S De Silva, Michael M Anderson, Kathryn Silva, Amanda Carette, Fabiano Orelli, Govind Bhagat, Ulf Klein
Signaling through the canonical nuclear factor-κB (NF-κB) pathway is critical for the generation and maintenance of mature B cells and for antigen-dependent B-cell activation. c-REL (rel) and RELA (rela) are the downstream transcriptional activators of the canonical NF-κB pathway. Studies of B cells derived from constitutional rel knockout mice and chimeric mice repopulated with rela(-/-) fetal liver cells provided evidence that the subunits can have distinct roles during B-cell development. However, the B cell-intrinsic functions of c-REL and RELA during B-cell generation and antigen-dependent B-cell activation have not been determined in vivo...
October 18, 2016: Immunology and Cell Biology
Philipp Kron, Michael Linecker, Perparim Limani, Andrea Schlegel, Patryk Kambakamba, Jean-Marie Lehn, Claude Nicolau, Rolf Graf, Bostjan Humar, Pierre-Alain Clavien
: Interaction between sinusoidal endothelial cells and hepatocytes is a prerequisite for liver function. Upon tissue loss, both liver cell populations need to be regenerated. Repopulation occurs in a coordinated pattern, first through the regeneration of parenchyme (hepatocytes), which then produces vascular endothelial growth factor (VEGF) to enable the subsequent angiogenic phase. The signals that instruct hepatocytes to induce timely VEGF remain unidentified. Given that liver is highly vascularized, we reasoned that fluctuations in oxygenation after tissue loss may contribute to the coordination between hepatocyte and sinusoidal endothelial cell proliferation...
September 15, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Bruna Araujo David, Rafael Machado Rezende, Maísa Mota Antunes, Mônica Morais Santos, Maria Alice Freitas Lopes, Ariane Barros Diniz, Rafaela Vaz Sousa Pereira, Sarah Cozzer Marchesi, Débora Moreira Alvarenga, Brenda Naemi Nakagaki, Alan Moreira Araújo, Daniela Silva Dos Reis, Renata Monti Rocha, Pedro Elias Marques, Woo-Yong Lee, Justin Deniset, Pei Xiong Liew, Stephen Rubino, Laura Cox, Vanessa Pinho, Thiago Mattar Cunha, Gabriel Rocha Fernandes, André Gustavo Oliveira, Mauro Martins Teixeira, Paul Kubes, Gustavo Batista Menezes
BACKGROUND & AIMS: Resident macrophages are derived from yolk sac precursors and seed the liver during embryogenesis. Native cells may be replaced by bone marrow precursors during extensive injuries, irradiation and infections. We investigated the liver populations of myeloid immune cells and their location as well as the dynamics of phagocyte repopulation after full depletion. The effects on liver function due to the substitution of original phagocytes by bone marrow-derived surrogates were also examined...
August 25, 2016: Gastroenterology
Fuqin Fan, Zhixiang He, Lu-Lu Kong, Qinghua Chen, Quan Yuan, Shihao Zhang, Jinjin Ye, Hao Liu, Xiufeng Sun, Jing Geng, Lunzhi Yuan, Lixin Hong, Chen Xiao, Weiji Zhang, Xihuan Sun, Yunzhan Li, Ping Wang, Lihong Huang, Xinrui Wu, Zhiliang Ji, Qiao Wu, Ning-Shao Xia, Nathanael S Gray, Lanfen Chen, Cai-Hong Yun, Xianming Deng, Dawang Zhou
Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration...
August 17, 2016: Science Translational Medicine
Trine A Kristiansen, Elin Jaensson Gyllenbäck, Alya Zriwil, Tomas Björklund, Jeremy A Daniel, Ewa Sitnicka, Shamit Soneji, David Bryder, Joan Yuan
Hematopoietic stem cells (HSCs) undergo a functional switch in neonatal mice hallmarked by a decrease in self-renewing divisions and entry into quiescence. Here, we investigated whether the developmental attenuation of B-1a cell output is a consequence of a shift in stem cell state during ontogeny. Using cellular barcoding for in vivo single-cell fate analyses, we found that fetal liver definitive HSCs gave rise to both B-1a and B-2 cells. Whereas B-1a potential diminished in all HSCs with time, B-2 output was maintained...
August 16, 2016: Immunity
Ludi Zhang, Yanjiao Shao, Lu Li, Feng Tian, Jin Cen, Xiaotao Chen, Dan Hu, Yan Zhou, Weifen Xie, Yunwen Zheng, Yuan Ji, Mingyao Liu, Dali Li, Lijian Hui
Hereditary tyrosinemia type I (HT1) is caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (Fah). Fah-deficient mice and pigs are phenotypically analogous to human HT1, but do not recapitulate all the chronic features of the human disorder, especially liver fibrosis and cirrhosis. Rats as an important model organism for biomedical research have many advantages over other animal models. Genome engineering in rats is limited till the availability of new gene editing technologies. Using the recently developed CRISPR/Cas9 technique, we generated Fah(-/-) rats...
2016: Scientific Reports
Raymond D Hickey, Shennen A Mao, Jaime Glorioso, Faysal Elgilani, Bruce Amiot, Harvey Chen, Piero Rinaldo, Ronald Marler, Huailei Jiang, Timothy R DeGrado, Lukkana Suksanpaisan, Michael K O'Connor, Brittany L Freeman, Samar H Ibrahim, Kah Whye Peng, Cary O Harding, Chak-Sum Ho, Markus Grompe, Yasuhiro Ikeda, Joseph B Lillegard, Stephen J Russell, Scott L Nyberg
We tested the hypothesis that ex vivo hepatocyte gene therapy can correct the metabolic disorder in fumarylacetoacetate hydrolase-deficient (Fah(-/-)) pigs, a large animal model of hereditary tyrosinemia type 1 (HT1). Recipient Fah(-/-) pigs underwent partial liver resection and hepatocyte isolation by collagenase digestion. Hepatocytes were transduced with one or both of the lentiviral vectors expressing the therapeutic Fah and the reporter sodium-iodide symporter (Nis) genes under control of the thyroxine-binding globulin promoter...
July 27, 2016: Science Translational Medicine
Franziska Mußbach, Utz Settmacher, Olaf Dirsch, Chichi Xie, Uta Dahmen
BACKGROUND: Organ engineering is a new innovative strategy to cope with two problems: the need for physiological models for pharmacological research and donor organs for transplantation. A functional scaffold is generated from explanted organs by removing all cells (decellularization) by perfusing the organ with ionic or nonionic detergents via the vascular system. Subsequently the acellular scaffold is reseeded with organ-specific cells (repopulation) to generate a functional organ. SUMMARY: This review gives an overview of the state of the art describing the decellularization process, the subsequent quality assessment, the repopulation techniques and the functional assessment...
July 27, 2016: European Surgical Research. Europäische Chirurgische Forschung. Recherches Chirurgicales Européennes
Preeti Viswanathan, Priya Gupta, Sorabh Kapoor, Sanjeev Gupta
BACKGROUND: & Aims: For liver-directed cell therapy, efficient engraftment of transplanted cells is critical. This study delineated whether anti-inflammatory and endothelial disrupting properties of thalidomide could promote transplanted cell engraftment and proliferation in liver. METHODS: We used dipeptidyl peptidase IV-deficient rats for cell transplantation studies, including gene expression analysis, morphological tissue analysis, serological assays, cell culture assays, and assays of transplanted cell engraftment and proliferation...
July 12, 2016: Journal of Hepatology
Naoki Tanimizu, Norihisa Ichinohe, Masayuki Ishii, Junichi Kino, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka
It has been proposed that tissue stem cells supply multiple epithelial cells in mature tissues and organs. However, it is unclear whether tissue stem cells generally contribute to cellular turnover in normal healthy organs. Here we show that liver progenitors distinct from bipotent liver stem/progenitor cells (LPCs) persistently exist in mouse livers and potentially contribute to tissue maintenance. We found that, in addition to LPCs isolated as EpCAM(+) cells, liver progenitors were enriched in CD45(-) TER119(-) CD31(-) EpCAM(-) ICAM-1(+) fraction isolated from late-fetal and postnatal livers...
July 4, 2016: Stem Cells
Edwin C Y Chow, Jason Z Ya Wang, Holly P Quach, Hui Tang, David C Evans, Albert P Li, Jose Silva, K Sandy Pang
Chimeric mouse liver models are useful in vivo tools for human drug metabolism studies; however, liver integrity and the microcirculation remain largely uninvestigated. Hence, we conducted liver perfusion studies to examine these attributes in FRGN [Fah(-/-), Rag2(-/-), and Il2rg(-/-), NOD strain] livers (control) and chimeric livers repopulated with mouse (mFRGN) or human (hFRGN) hepatocytes. In single-pass perfusion studies (2.5 ml/min), outflow dilution profiles of noneliminated reference indicators ((51)Cr-RBC, (125)I-albumin, (14)C-sucrose, and (3)H-water) revealed preservation of flow-limited distribution and reduced water and albumin spaces in hFRGN livers compared with FRGN livers, a view supported microscopically by tightly packed sinusoids...
September 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Crystal Dykstra, Amanda J Lee, Evan J Lusty, Mira M Shenouda, Mahsa Shafai, Fatemeh Vahedi, Marianne V Chew, Stephen Collins, Ali A Ashkar
BACKGROUND: Humanized mouse models are an increasingly popular preclinical model to study the human immune response in a biological system. There are a variety of protocols to generate these mice, each differing in the strain of the recipient, source of hematopoietic stem cells, and mode of transplantation. Though there is well-documented reconstitution information regarding the spleen, blood, and bone marrow, there is little information regarding reconstitution of the lymph node and liver...
2016: BMC Immunology
Shan Yu, Joselyn N Allen, Adwitia Dey, Limin Zhang, Gayathri Balandaram, Mary J Kennett, Mingcan Xia, Na Xiong, Jeffrey M Peters, Andrew Patterson, Pamela A Hankey-Giblin
Obesity is a chronic inflammatory disease mediated in large part by the activation of inflammatory macrophages. This chronic inflammation underlies a whole host of diseases including atherosclerosis, hepatic steatosis, insulin resistance, type 2 diabetes, and cancer, among others. Macrophages are generally classified as either inflammatory or alternatively activated. Some tissue-resident macrophages are derived from yolk sac erythromyeloid progenitors and fetal liver progenitors that seed tissues during embryogenesis and have the ability to repopulate through local proliferation...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Katja Thomas, Judith Eisele, Francisco Alejandro Rodriguez-Leal, Undine Hainke, Tjalf Ziemssen
OBJECTIVE: Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cells. Beyond long-term immunologic and clinical data, little is known about acute changes in immunologic and routine laboratory parameters and their clinical relevance during the initial alemtuzumab infusion. METHODS: Fifteen patients with highly active MS were recruited. In addition to parameters including heart rate, blood pressure, body temperature, and monitoring of adverse events, complete blood cell count, liver enzymes, kidney function, acute-phase proteins, serum cytokine profile, complement activation, peripheral immune cell distribution, and their potential of cytokine release were investigated prior to and after methylprednisolone and after alemtuzumab on each day of alemtuzumab infusion...
June 2016: Neurology® Neuroimmunology & Neuroinflammation
Susanne Rohn, Jan Schroeder, Henriette Riedel, Dietrich Polenz, Katarina Stanko, Anja Reutzel-Selke, Peter Tang, Lydia Brusendorf, Nathanael Raschzok, Peter Neuhaus, Johann Pratschke, Birgit Sawitzki, Igor M Sauer, Martina T Mogl
OBJECTIVES: Stable long-term functioning of liver cells after transplantation in humans is still not achieved successfully. A new approach for successful engraftment of liver cells may be the transplantation of syngeneic cells into an allogeneic liver graft. We therefore developed a new rat model for combined liver and liver cell transplantation (cLCTx) under stable immunosuppression. MATERIALS AND METHODS: After inducing a mitotic block, liver grafts from female donor rats (Dark Agouti) were transplanted into female recipients (Lewis)...
May 20, 2016: Cells, Tissues, Organs
Panagiotis Maghsoudlou, Fanourios Georgiades, Holly Smith, Anna Milan, Panicos Shangaris, Luca Urbani, Stavros P Loukogeorgakis, Benedetta Lombardi, Giuseppe Mazza, Charlotte Hagen, Neil J Sebire, Mark Turmaine, Simon Eaton, Alessandro Olivo, Jasminka Godovac-Zimmermann, Massimo Pinzani, Paul Gissen, Paolo De Coppi
Hepatic tissue engineering using decellularized scaffolds is a potential therapeutic alternative to conventional transplantation. However, scaffolds are usually obtained using decellularization protocols that destroy the extracellular matrix (ECM) and hamper clinical translation. We aim to develop a decellularization technique that reliably maintains hepatic microarchitecture and ECM components. Isolated rat livers were decellularized by detergent-enzymatic technique with (EDTA-DET) or without EDTA (DET). Histology, DNA quantification and proteomics confirmed decellularization with further DNA reduction with the addition of EDTA...
2016: PloS One
Suzy Fayez Ewida, Asmaa Gaber Abdou, Amal Abd El-Rasol Elhosary, Shaimaa Abd El-Ghane Metawe
It is still a matter of debate as to whether in vitro mesenchymal stem cell (MSC)-derived hepatocytes may efficiently repopulate a host liver to provide adequate functional substitution. The aim of this study is to assess the efficacy and consistency of in vitro hepatic differentiation from Wharton jelly-derived MSCs, and to validate their therapeutic potential in experimentally induced liver fibrosis compared with nondifferentiated MSCs. Forty adult male albino rats were divided into 4 main groups: (I) normal control group; (II) carbon tetrachloride (CCl4)-treated group (injected CCl4 solution twice a week for 8 wk); (III) MSC-treated group (a single intravenous dose of MSCs from human umbilical cord at the fourth week of induction of fibrosis); and (IV) hepatocyte-like stem cells (HLCs)-treated group (a single intravenous dose of MSCs after in vitro conversion to hepatocyte at the fourth week of induction of fibrosis)...
May 5, 2016: Applied Immunohistochemistry & Molecular Morphology: AIMM
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