PMID- 27067455
OWN - NLM
STAT- MEDLINE
DCOM- 20180423
LR  - 20180710
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 65
IP  - 1
DP  - 2016 Jul
TI  - A new fluorescence-based optical imaging method to non-invasively monitor hepatic
      myofibroblasts in vivo.
PG  - 75-83
LID - S0168-8278(16)30104-0 [pii]
LID - 10.1016/j.jhep.2016.03.021 [doi]
AB  - BACKGROUND & AIMS: Currently, staging of fibrosis in preclinical rodent liver
      fibrosis models is achieved histologically. Many animals are used at multiple
      time-points to assess disease progression or therapeutic responses. Hepatic
      myofibroblasts promote liver fibrosis therefore quantifying these cells in vivo
      could assess disease or predict therapeutic responses in mice. We fluorescently
      labelled a single chain antibody (C1-3) that binds hepatic myofibroblasts to
      monitor fibrogenesis in vivo. METHODS: CCl4 was used to induce acute liver injury
      in WT and cRel(-/-) mice. Bile duct ligation was used to model chronic fibrosis. 
      Hepatic myofibroblasts were depleted using a liposome-drug delivery system or
      chemically with sulfasalazine. An IVIS(R) spectrum visualised
      fluorophore-conjugated C1-3 in vivo. RESULTS: IVIS detection of fluorescently
      labelled-C1-3 but not a control antibody discriminates between fibrotic and
      non-fibrotic liver in acute and chronic liver fibrosis models. cRel(-/-) mice
      have a fibro-protective phenotype and IVIS signal is reduced in CCl4 injured
      cRel(-/-) mice compared to wild-type. In vivo imaging of fluorescently
      labelled-C1-3 successfully predicts reductions in hepatic myofibroblast numbers
      in fibrotic liver disease in response to therapy. CONCLUSIONS: We report a novel 
      fluorescence imaging method to assess murine hepatic myofibroblast numbers in
      vivo during liver fibrosis and after therapy. We also describe a novel liposomal 
      antibody targeting system to selectively deliver drugs to hepatic myofibroblasts 
      in vivo. C1-3 binds human hepatic myofibroblast therefore imaging labelled-C1-3
      could be used for clinical studies in man to help stage fibrosis, demonstrate
      efficacy of drugs that promote hepatic myofibroblast clearance or predict early
      therapeutic responses. LAY SUMMARY: In response to damage and injury scars
      develop in the liver and the main cell that makes the scar tissue is the hepatic 
      myofibroblast (HM). C1-3 is an antibody fragment that binds to the scar forming
      HM. We have fluorescently labelled C1-3 and given it to mice that have either
      normal or scarred livers (which contain HM) and then used a machine called an in 
      vivo imaging system (IVIS) that takes pictures of different wavelengths of light,
      to visualise the antibody binding to HM inside the living mouse. Using
      fluorescently labelled C1-3 we can assess HM numbers in the injured liver and
      monitor response to therapy. We have also used C1-3 to target drugs encapsulated 
      in lipid carriers (liposomes) to the HM to kill the HM and reduce the liver
      disease.
CI  - Copyright (c) 2016 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Luli, Saimir
AU  - Luli S
AD  - Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University,
      Newcastle upon Tyne NE2 4HH, UK.
FAU - Di Paolo, Daniela
AU  - Di Paolo D
AD  - Experimental Therapy Unit, Laboratory of Oncology, Istituto Giannina Gaslini,
      Genoa, Italy.
FAU - Perri, Patrizia
AU  - Perri P
AD  - Experimental Therapy Unit, Laboratory of Oncology, Istituto Giannina Gaslini,
      Genoa, Italy.
FAU - Brignole, Chiara
AU  - Brignole C
AD  - Experimental Therapy Unit, Laboratory of Oncology, Istituto Giannina Gaslini,
      Genoa, Italy.
FAU - Hill, Stephen J
AU  - Hill SJ
AD  - Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University,
      Newcastle upon Tyne NE2 4HH, UK.
FAU - Brown, Helen
AU  - Brown H
AD  - Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University,
      Newcastle upon Tyne NE2 4HH, UK.
FAU - Leslie, Jack
AU  - Leslie J
AD  - Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University,
      Newcastle upon Tyne NE2 4HH, UK.
FAU - Marshall, H L
AU  - Marshall HL
AD  - Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University,
      Newcastle upon Tyne NE2 4HH, UK.
FAU - Wright, Matthew C
AU  - Wright MC
AD  - Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University,
      Newcastle upon Tyne NE2 4HH, UK.
FAU - Mann, Derek A
AU  - Mann DA
AD  - Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University,
      Newcastle upon Tyne NE2 4HH, UK.
FAU - Ponzoni, Mirco
AU  - Ponzoni M
AD  - Experimental Therapy Unit, Laboratory of Oncology, Istituto Giannina Gaslini,
      Genoa, Italy.
FAU - Oakley, Fiona
AU  - Oakley F
AD  - Fibrosis Research Group, Institute of Cellular Medicine, Newcastle University,
      Newcastle upon Tyne NE2 4HH, UK. Electronic address:
      fiona.oakley@newcastle.ac.uk.
LA  - eng
GR  - G0900535/Medical Research Council/United Kingdom
GR  - MR/L016354/1/Medical Research Council/United Kingdom
GR  - NC/K500471/1/National Centre for the Replacement, Refinement and Reduction of
      Animals in Research/International
GR  - MR/K0019494/1/Medical Research Council/United Kingdom
GR  - 087961/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160409
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
SB  - IM
MH  - Animals
MH  - Bile Ducts
MH  - Fluorescence
MH  - Humans
MH  - Liver
MH  - Liver Cirrhosis
MH  - Mice
MH  - *Myofibroblasts
PMC - PMC4914605
OTO - NOTNLM
OT  - *Cell-targeting
OT  - *Fibrosis
OT  - *Hepatic myofibroblasts
OT  - *Mouse
OT  - *Non-invasive imaging
EDAT- 2016/04/14 06:00
MHDA- 2018/04/24 06:00
CRDT- 2016/04/13 06:00
PHST- 2015/08/21 00:00 [received]
PHST- 2016/03/03 00:00 [revised]
PHST- 2016/03/23 00:00 [accepted]
PHST- 2016/04/13 06:00 [entrez]
PHST- 2016/04/14 06:00 [pubmed]
PHST- 2018/04/24 06:00 [medline]
AID - S0168-8278(16)30104-0 [pii]
AID - 10.1016/j.jhep.2016.03.021 [doi]
PST - ppublish
SO  - J Hepatol. 2016 Jul;65(1):75-83. doi: 10.1016/j.jhep.2016.03.021. Epub 2016 Apr
      9.