Hepatic Targeting of Transplanted Liver Sinusoidal Endothelial Cells in Intact Mice *

Benten, Daniel; Follenzi, Antonia; Bhargava, Kuldeep K.; Kumaran, Vinay; Palestro, Christopher J.; Gupta, Sanjeev

doi:10.1002/hep.20746

Cited by 45 publications

(50 citation statements)

References 46 publications

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“…Hepatocytes were isolated by 2-step collagenase perfusion, and 2 ϫ 10 6 viable cells were injected immediately in 0.2 mL RPMI 1640 medium into the splenic pulp as described. 4 The Animal Care and Use Committee at Albert Einstein College of Medicine approved protocols in compliance with National Research Council guidelines (Guide for the Care and Use of Laboratory Animals; United States Public Health Service publication, revised 1996).…”

Section: Methodsmentioning

confidence: 99%

“…[2][3][4] It was noteworthy that transplanted cells did not proliferate in the normal liver, where cell turnover is minimal, although, depending on the extent of injury in native cells, proliferation in healthy transplanted cells was activated. 5,6 In this way, transplanted cells could repopulate the liver, where in specific situations the kinetics of liver repopulation reflected loss of native hepatocytes.…”

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confidence: 99%

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Hepatocyte transplantation and drug-induced perturbations in liver cell compartments

Wu¹,

Joseph²,

Berishvili³

et al. 2008

Hepatology

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The potential for organ damage after using drugs or chemicals is a critical issue in medicine. To delineate mechanisms of drug-induced hepatic injury, we used transplanted cells as reporters in dipeptidyl peptidase IV-deficient mice. These mice were given phenytoin and rifampicin for 3 days, after which monocrotaline was given followed 1 day later by intrasplenic transplantation of healthy C57BL/6 mouse hepatocytes. We examined endothelial and hepatic damage by serologic or tissue studies and assessed changes in transplanted cell engraftment and liver repopulation by histochemical staining for dipeptidyl peptidase IV. Monocrotaline caused denudation of the hepatic sinusoidal endothelium and increased serum hyaluronic acid levels, along with superior transplanted cell engraftment. Together, phenytoin, rifampicin, and monocrotaline caused further endothelial damage, reflected by greater improvement in cell engraftment. Phenytoin, rifampicin, and monocrotaline produced injury in hepatocytes that was not apparent after conventional tissue studies. This led to transplanted cell proliferation and extensive liver repopulation over several weeks, which was more efficient in males compared with females, including greater induction by phenytoin and rifampicin of cytochrome P450 3A4 isoform that converts monocrotaline to toxic intermediates. Through this and other possible mechanisms, monocrotaline-induced injury in the endothelial compartment was retargeted to simultaneously involve hepatocytes over the long term. Moreover, after this hepatic injury, native liver cells were more susceptible to additional pro-oxidant injury through thyroid hormone, which accelerated the kinetics of liver repopulation. Conclusion: Transplanted reporter cells will be useful for obtaining insights into homeostatic mechanisms involving liver cell compartments, whereas targeted injury in hepatic endothelial and parenchymal cells with suitable drugs will also help advance liver cell therapy. ( T o obtain fresh paradigms in tissue homeostasis after exposure to drugs or chemicals, 1 we considered that reporter cells will help elucidate perturbations in the liver, because genetically marked reporter cells can be inserted into liver compartments, including the parenchyma or hepatic endothelium. 2-4 It was noteworthy that transplanted cells did not proliferate in the normal liver, where cell turnover is minimal, although, depending on the extent of injury in native cells, proliferation in healthy transplanted cells was activated. 5,6 In this way, transplanted cells could repopulate the liver, where in specific situations the kinetics of liver repopulation reflected loss of native hepatocytes. [7][8][9] In healthy animals, genotoxic manipulations were particularly effective in promoting such liver repopulation with healthy cells. However, further insights are necessary to obtain pharmacologic approaches for repopulating the liver, particularly for clinical applications.To develop cell compartment-specific hepatic perturbations, we used monocrotaline (...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Hepatocyte transplantation and drug-induced perturbations in liver cell compartments

Wu¹,

Joseph²,

Berishvili³

et al. 2008

Hepatology

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“…23 RBCs were lysed for 5 minutes on ice. Kupffer cells (KCs) were selected by anti-CD11b, hematopoietic cells were removed by anti-CD45, and LSECs were isolated by immunomagnetic sorting (Miltenyi Biotec; supplemental Methods).…”

Section: Cellsmentioning

confidence: 99%

Role of bone marrow transplantation for correcting hemophilia A in mice

Follenzi

Raut

Merlin

et al. 2012

Blood

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To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)-derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. IntroductionHemophilia A is characterized by inability to clot blood because of FVIII gene mutations and deficiency of this coagulation factor. 1 The potential for cell and gene therapy in hemophilia A is highly attractive because even small amounts of FVIII may substantially decrease bleeding risk. This requires sound knowledge of cell types capable of replacing FVIII, especially within proximity of von Willebrand factor (vWF), which protects FVIII from degradation. 2 However, the cell-type origin of FVIII has been controversial. 3 Correction of hemophilia after orthotopic liver transplantation (OLT) but not after kidney transplantation, despite FVIII mRNA expression in both organs, 3,4 indicated that liver was a major site for FVIII production. Recently, the cell transplantation approach established that of various liver cell types, liver sinusoidal endothelial cells (LSECs) replaced FVIII in hemophilia mice. 5,6 Nonetheless, extrahepatic organs probably contributed in FVIII production, as indicated by FVIII synthesis in spleen, lungs, or pancreatic islets. [6][7][8] This was in agreement with lack of plasma FVIII deficiency after OLT with donor liver from dogs or people with hemophilia A because such donor liver cells would not have synthesized or secreted FVIII. 9,10 Therefore, whether nonendothelial cells, and cells in extrahepatic organs, could also produce FVIII was not excluded. For instance, macrophages, which originate in bone marrow (BM), and contained FVIII mRNA, 11 could be such a candidate. Although FVIII was cloned from T cells, 12 and transplantation of lymphatic tissue was thought to correct hemophilia in dogs, 13 whether lymphocytes did express FVIII was uncertain, because correction of hemophilia by transplanted organs (eg, spleen) included other cell types. 7,14,15 Because BM cells may generate multiple lineages, the potential of BM-derived cells in FVIII production seemed relevant to us. Previously, BM transplantation studies in hemophilia A, 40 years ago, were limited to just 3 dogs and 2 persons. [16][17][18][19] BM transplantation in hemophilia dogs was carefully performed, although there were limitations, such as suboptimal allograft tolerance, lack of studies showing engraftment and generation of various BM cell types, absence of FVIII expression analysis in donor BM-derived cells,...

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“…To address whether defective SECs could be replaced with transplanted ones, SECs from transgenic donor mice where a green fluorescent protein reporter was expressed in SECs by virtue of the Tie2 endothelial promoter were injected into recipient mice to assess engraftment in the hepatic sinusoidal bed. 68 Transplanted liver SECs proliferated over time with progressive replacement of the liver endothelium, such that approximately 20% of the endothelial compartment was replaced after 3 months. 69 Transplanted cells became integrated in the liver structure, were distinct from other sinusoidal liver cells, and retained normal function, including DiI-Ac-LDL incorporation and production of coagulation Factor VIII.…”

Section: Emerging Therapies For Vascular Diseases Of the Livermentioning

confidence: 99%

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

2008

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Portal hypertension and its complications account for the majority of morbidity and mortality that occurs in patients with cirrhosis. In addition to portal hypertension, a number of other vascular syndromes are also of great importance, especially the ischemia-reperfusion (IR) injury. With the identification of major vascular defects that could account for many of the clinical sequelae of these syndromes, the liver vasculature field has now integrated very closely with the broader vascular biology discipline. In that spirit, the Vascular Cell Signaling Mediated by NO. Endothelial cells (ECs) produce NO through the enzyme endothelial NO synthase (eNOS). NO then regulates important vascular functions, such as vascular tone, angiogenesis, and arterial remodeling. 1 eNOS is regulated in a multiprotein complex (Fig. 1), which includes the activating kinase, Akt1 and putative negative regulator caveolin-1 (Cav-1). Although eNOS Ϫ/Ϫ mice evidence impaired angiogenesis, overexpression of a constitutively active allele of eNOS that mimics the phosphorylated and active state rescues these angiogenic defects. 2 Because eNOS is an EC-specific Akt substrate, ECs from mice lacking the Akt1 isoform also have defects in eNOS phosphorylation, NO production, and angiogenesis which are correspondingly rescued by Akt1 overexpression. 3 One key mechanism by which the Akt-eNOS axis promotes angiogenesis in vivo is through mobilization of endothelial progenitor cells and EC migration to sites of vascular injury. In contradistinction to AKT, Cav-1 is a negative regulator of eNOS. Mice deficient in Cav-1 have defective mechanotransduction, calcium signaling, prostacyclin production, and elevated NO production indicating that endothelial Cav-1 also importantly regulates vascular function by regulating eNOS and other signaling pathways. 4 Upon its generation in ECs, NO also acts on adjacent vascular effector cells to modulate vascular tone, cellular proliferation, apoptosis, migration, and synthesis of extracellular matrix (Fig. 2). NO acts in part by stimulating soluble guanylate cyclase (sGC) to produce intracellular Abbreviations: Cav-

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Hepatic Targeting of Transplanted Liver Sinusoidal Endothelial Cells in Intact Mice *

Cited by 45 publications

References 46 publications

Hepatocyte transplantation and drug-induced perturbations in liver cell compartments

Hepatocyte transplantation and drug-induced perturbations in liver cell compartments

Role of bone marrow transplantation for correcting hemophilia A in mice

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

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