Studies of liver repopulation using the dipeptidyl peptidase IV-deficient rat and other rodent recipients: Cell size and structure relationships regulate capacity for increased transplanted hepatocyte mass in the liver lobule

Rajvanshi, Pankaj; Kerr, Andrew; Bhargava, Kuldeep K.; Burk, Robert D.; Gupta, Sanjeev

doi:10.1002/hep.510230313

Cited by 145 publications

(60 citation statements)

References 12 publications

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“…Cell-vascular relationships play critical roles in the intrahepatic targeting of hepatocytes, which are larger than EC and are more readily restricted to the liver. 27,33 Similarly, myocardial targeting of mesenchymal stem cells depends on vessel and cell size differences, because intravenous injection entraps cells in lungs, and intracardiac injection is necessary for depositing cells in the myocardium. 39 LSEC targeting after systemic intravenous, intraportal, or intrasplenic injections was accounted for in part by mechanical cell entrapment in vascular beds.…”

Section: Discussionmentioning

confidence: 99%

“…26 However, if LSEC escaped from the liver by exiting through central veins as a result of their small size, engraftment of LSEC could be affected. 27 Therefore, we labeled LSEC with radionuclide, metabolic, or transgene markers and used donor cells natively expressing the green fluorescent protein (GFP) under control of endothelial-specific Tie-2 promoter 28,29 to establish cell-targeting mechanisms.…”

Section: E Ndothelial Cells (Ec) Play Critical Roles In Orga-mentioning

confidence: 99%

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

et al. 2005

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Targeting of cells to specific tissues is critical for cell therapy. To study endothelial cell targeting, we isolated mouse liver sinusoidal endothelial cells (LSEC) and examined cell biodistributions in animals. To identify transplanted LSEC in tissues, we labeled cells metabolically with DiIconjugated acetylated low density lipoprotein particles (DiI-Ac-LDL) or 111 Indium-oxine, used LSEC from Rosa26 donors expressing ␤-galactosidase or Tie-2-GFP donors with green fluorescent protein (GFP) expression, and tranduced LSEC with a GFP-lentiviral vector. LSEC efficiently incorporated 111 Indium and DiI-Ac-LDL and expressed GFP introduced by the lentiviral vector. Use of radiolabeled LSEC showed differences in cell biodistributions in relation to the cell transplantation route. After intraportal injection, LSEC were largely in the liver (60 ؎ 13%) and, after systemic intravenous injection, in lungs (67 ؎ 9%); however, after intrasplenic injection, only some LSEC remained in the spleen (29 ؎ 10%; P < .01), whereas most LSEC migrated to the liver or lungs. Transplanted LSEC were found in the liver, lungs, and spleen shortly after transplantation, whereas longer-term cell survival was observed only in the liver. Transplanted LSEC were distinct from Kupffer cells with expression of Tie-2 promoter-driven GFP and of CD31, without F4/80 reactivity. In further studies using radiolabeled LSEC, we established that the manipulation of receptor-mediated cell adhesion in liver sinusoids or the manipulation of blood flow-dependent cell exit from sinusoids improved intrahepatic retention of LSEC to 89 ؎ 7% and 89 ؎ 5%, respectively (P < .01). In conclusion, the targeting of LSEC to the liver and other organs is directed by vascular bed-specific mechanisms, including blood flow-related processes, and cell-specific factors. These findings may facilitate analysis of LSEC for cell and gene therapy applications. (HEPATOLOGY 2005;42:140-148.)

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Section: Discussionmentioning

confidence: 99%

Section: E Ndothelial Cells (Ec) Play Critical Roles In Orga-mentioning

confidence: 99%

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

et al. 2005

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“…8 Previous studies 8,9 established that transplantation of hepatocytes into hepatic sinusoids was most effective for survival and function of transplanted cells in the liver. However, because the capacity of the hepatic vascular bed for transplanted cells is small, 10 this posed questions about the feasibility of significant hepatic support by this method. Cell transplantation in liver sinusoids may even be undesirable in ALF because occlusion of blood flow by transplanted cells might worsen hepatic injury.…”

mentioning

confidence: 99%

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Bandi

Joseph

Berishvili

et al. 2011

The American Journal of Pathology

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Superior insights into molecular mechanisms of liver failure, which are not fully understood, will help strategies for inducing liver regeneration. We examined hepatotoxic mechanisms in mice homozygous for the severe combined immune deficiency mutation in the protein kinase, DNA-activated, catalytic polypeptide. Mice were treated with rifampicin, phenytoin, and monocrotaline. The ensuing acute liver failure was characterized by serological, histological, and mRNA studies. Subsequently, we studied whether transplantation of hepatocytes could rescue animals with liver failure. We found extensive liver damage in these animals, with mortality over several days. The expression of multiple hepatic genes was rapidly altered, including those representing pathways in oxidative/metabolic stress, inflammation, DNA damage-repair, and ataxia telangiectasia mutant (Atm) signaling pathways. This led to liver cell growth arrest involving cyclin-dependent kinase inhibitor 1A. Transplantation of hepatocytes with microcarriers in the peritoneal cavity efficiently rescued animals with liver failure. Molecular abnormalities rapidly reversed, including in hepatic Atm and downstream signaling pathways; and residual hepatocytes overcame cyclin-dependent kinase inhibitor 1A-induced cell growth arrest. Reseeding of the liver with transplanted hepatocytes was not required for rescue because native hepatocytes overcame cell growth-arrest to regenerate the liver. This likely resulted from paracrine signaling from hepatocytes in the peritoneal cavity. We concluded that Atm signaling Drug-induced liver injury (DILI) often results in acute liver failure (ALF). 1 Acetaminophen (APAP) is the leading offender in causing ALF; however, despite extensive work, mechanisms of DILI by APAP are incompletely understood. [2][3][4][5] The identification of molecular pathways initiating or amplifying DILI will be highly significant for drug development and for preventing and/or treating ALF. After exposure to hepatotoxic drugs, perturbations in cell stress and toxicity pathways assume prominence. However, more information is required regarding intracellular signaling pathways that impart susceptibility to DILI. Similarly, more information is required regarding failure of liver regeneration in ALF. Nevertheless, establishing these mechanisms has been difficult in the available animal models of ALF. For instance, after exposure to toxic drugs or chemicals, some animals may exhibit rapid and irreversible mortality (eg, within 24 -30 hours after APAP), whereas other animals may recover spontaneously.

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“…76 They entered through portal vein branches, were entrapped in proximal hepatic sinusoids because of their larger size, and consequently were distributed predominantly to periportal regions of the hepatic lobule. 77 Most of the entrapped hepatocytes were destroyed by activated phagocytotic responses. 78 The remaining cells translocated from sinusoids into liver plates within 20 h after cell transplantation, through a process involving disruption of the sinusoidal endothelium, release of vascular endothelial growth factor (VEGF) by both host and transplanted hepatocytes.…”

Section: Hepatocyte Transplantation Mechanismsmentioning

confidence: 99%

“…78 The remaining cells translocated from sinusoids into liver plates within 20 h after cell transplantation, through a process involving disruption of the sinusoidal endothelium, release of vascular endothelial growth factor (VEGF) by both host and transplanted hepatocytes. 77,79,80 Subsequently, translocated cells integrated into the liver parenchyma, regained their polarity with the formation of gap junctions and bile canaliculi between transplanted and host hepatocytes within about 1 week, without any significant proliferation in adult animals and were functional throughout the life of animals. 74,75,81 Overall, only 20-30% of transplanted hepatocytes integrated into the liver.…”

Section: Hepatocyte Transplantation Mechanismsmentioning

confidence: 99%

Liver gene therapy: advances and hurdles

Nguyen

Ferry

2004

Gene Ther

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Studies of liver repopulation using the dipeptidyl peptidase IV-deficient rat and other rodent recipients: Cell size and structure relationships regulate capacity for increased transplanted hepatocyte mass in the liver lobule

Cited by 145 publications

References 12 publications

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

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

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Liver gene therapy: advances and hurdles

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