Use of Indium-111–Labeled Hepatocytes to Determine the Biodistribution of Transplanted Hepatocytes Through Portal Vein Infusion

Bohnen, Nicolaas I.; Charron, Martin; Reyes, Jorgé; Rubinstein, Wendy S.; Strom, Stephen C.; Swanson, Dennis P.; Towbin, Richard B.

doi:10.1097/00003072-200006000-00012

Cited by 66 publications

(40 citation statements)

References 11 publications

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“…28,29 Previous studies have shown that rodent and human hepatocytes effectively incorporate 111 In and 99m Tc labels. 31,33,36 Similarly, leukocytes and other cells incorporate 111 In and 99m Tc labels, and bone marrow-derived mesenchymal stem cells incorporate 99m Tc-exametazime. [37][38][39] In contrast, mouse and rat LSEC incorporated 111 In-oxine but not 99m Tc.…”

Section: Discussionmentioning

confidence: 99%

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%

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

et al. 2005

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“…After re-establishing intercellular contacts with neighboring hepatocytes and connecting to the biliary and vascular systems, transplanted cells are functionally and histologically indistinguishable from endogenous hepatocytes [59]. Excellent evidence that the cells delivered via the portal vein do not readily pass through the liver to extrahepatic sites was provided when human hepatocytes, labeled with indium-111 oxyquinoline, were infused in a 5-year- old child with urea cycle defect [62]. …”

Section: Cell Dose and Route Of Administrationmentioning

confidence: 99%

“…Novel noninvasive methods to label and monitor cell survival and engraftment after transplantation are also currently under investigation [107]. As mentioned, radioisotopes have been successfully used in clinical settings to demonstrate hepatocyte distribution after transplantation [62]. In addition, MRIs of donor cells previously loaded with iron oxide particles [108,109] will likely be investigated in clinical transplants.…”

Section: Evaluation Of Sustained Engraftmentmentioning

confidence: 99%

Clinical Hepatocyte Transplantation: Practical Limits and Possible Solutions

et al. 2015

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Since the first human hepatocyte transplants (HTx) in 1992, clinical studies have clearly established proof of principle for this therapy as a treatment for patients with acquired or inherited liver disease. Although major accomplishments have been made, there are still some specific limitations to this technology, which, if overcome, could greatly enhance the efficacy and implementation of this therapy. Here, we describe what in our view are the most significant obstacles to the clinical application of HTx and review the solutions currently proposed. The obstacles of significance include the limited number and quality of liver tissues as a cell source, the lack of clinical grade reagents, quality control evaluation of hepatocytes prior to transplantation, hypothermic storage of cells prior to transplantation, preconditioning treatments to enhance engraftment and proliferation of donor cells, tracking or monitoring cells after transplantation, and the optimal immunosuppression protocols for transplant recipients.

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“…[ 111 In]indium oxine ( 111 In-oxine) has been widely accepted for safe radiolabeling of leukocytes to localize areas of inflammation. 6 -8 Moreover, 111 In-oxine has been used to determine the biodistribution of transplanted hepatocytes 9 or dendritic cells. 10,11 Therefore, we investigated whether radioactive labeling with 111 In-oxine might provide a clinically applicable tool to monitor the fate of transplanted EPCs in living rats after myocardial infarction.…”

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confidence: 99%

Assessment of the Tissue Distribution of Transplanted Human Endothelial Progenitor Cells by Radioactive Labeling

et al. 2003

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Background-Transplantation of endothelial progenitor cells (EPCs) improves vascularization and left ventricular functionafter experimental myocardial ischemia. However, tissue distribution of transplanted EPCs has not yet been monitored in living animals. Therefore, we tested whether radioactive labeling allows us to detect injected EPCs. Methods and Results-Human EPCs were isolated from peripheral blood, characterized by expression of endothelial marker proteins, and radioactively labeled with [ 111 In]indium oxine. EPCs (10 6 ) were injected in athymic nude rats 24 hours after myocardial infarction (nϭ8) or sham operation (nϭ8). Scintigraphic images were acquired after 1, 24, 48, and 96 hours after EPC injection. Animals were then killed, and specific radioactivity was measured in different tissues. At 24 to 96 hours after intravenous injection of EPCs, Ϸ70% of the radioactivity was localized in the spleen and liver, with only Ϸ1% of the radioactivity identified in the heart of sham-operated animals. After myocardial infarction, the heart-to-muscle radioactivity ratio increased significantly, from 1.02Ϯ0.19 in sham-operated animals to 2.03Ϯ0.37 after intravenous administration of EPCs. Injection of EPCs into the left ventricular cavity increased this ratio profoundly, from 2.69Ϯ1.54 in sham-operated animals to 4.70Ϯ1.55 (PϽ0.05) in rats with myocardial infarction. Immunostaining of cryosections from infarcted hearts confirmed that EPCs homed predominantly to the infarct border zone. Conclusions-Although only a small proportion of radiolabeled EPCs are detected in nonischemic myocardium, myocardial infarction increases homing of transplanted EPCs in vivo profoundly. Radiolabeling might eventually provide an useful tool for monitoring the fate of transplanted progenitor cells and for clinical cell therapy. (Circulation.

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Use of Indium-111–Labeled Hepatocytes to Determine the Biodistribution of Transplanted Hepatocytes Through Portal Vein Infusion

Abstract: These results indicate that In-111 labeling of hepatocytes is useful for the short-term noninvasive analysis of the biodistribution of transplanted hepatocytes.

Cited by 66 publications

References 11 publications

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

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

Clinical Hepatocyte Transplantation: Practical Limits and Possible Solutions

Assessment of the Tissue Distribution of Transplanted Human Endothelial Progenitor Cells by Radioactive Labeling

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