Phenotypic and functional characterization of macrophages with therapeutic potential generated from human cirrhotic monocytes in a cohort study.
OBJECTIVE
Macrophages have complex roles in the liver. The aim of this study was to compare profiles of human monocyte-derived macrophages between controls and cirrhotic patients, to determine whether chronic inflammation affects precursor number or the phenotype, with the eventual aim to develop a cell therapy for cirrhosis.


METHODS
Infusion of human macrophages in a murine liver fibrosis model demonstrated a decrease in markers of liver injury (alanine transaminase, bilirubin, aspartate transaminase) and fibrosis (transforming growth factor-β, α-smooth muscle actin, phosphatidylserine receptor) and an increase in markers of liver regeneration (matrix metalloproteinases [MMP]-9, MMP-12 and TNF-related weak inducer of apoptosis). CD14+ monocytes were then isolated from controls. Monocytes were matured into macrophages for 7 days using a Good Manufacturing Practice-compatible technique.


RESULTS
There was no significant difference between the mean number of CD14+ monocytes isolated from cirrhotic patients (n = 9) and controls (n = 10); 2.8 ± SEM 0.54 × 10(8) and 2.5 ± 0.56 × 10(8), respectively. The mean yield of mature macrophages cultured was also not significantly different between cirrhotic patients and controls (0.9 × 10(8) ± 0.38 × 10(8), with more than 90% viability and 0.65 × 10(8) ± 0.16 × 10(8), respectively. Maturation to macrophages resulted in up-regulation of a number of genes (MMP-9, CCL2, interleukin [IL]-10 and TNF-related weak inducer of apoptosis). A cytokine and chemokine polymerase chain reaction array, comparing the control and cirrhotic macrophages, revealed no statistically significant differences.


CONCLUSIONS
Macrophages can be differentiated from cirrhotic patients' apheresis-derived CD14 monocytes and develop the same pro-resolution phenotype as control macrophages, indicating their suitability for clinical therapy.
MRC Centre for Regenerative Medicine, Max Born Crescent, University of Edinburgh, Edinburgh, United Kingdom.
Joanna K
JK
Moore
MRC Centre for Regenerative Medicine, Max Born Crescent, University of Edinburgh, Edinburgh, United Kingdom.
Alison C
AC
Mackinnon
MRC Centre for Regenerative Medicine, Max Born Crescent, University of Edinburgh, Edinburgh, United Kingdom.
Dvina
D
Wojtacha
Scottish Universities Life Sciences Alliance (SULSA), Max Born Crescent, University of Edinburgh, Edinburgh, United Kingdom.
Caroline
C
Pope
Research, Development and Innovation, Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, United Kingdom.
Alasdair R
AR
Fraser
Research, Development and Innovation, Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, United Kingdom.
Paul
P
Burgoyne
Research, Development and Innovation, Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, United Kingdom.
Laura
L
Bailey
Research, Development and Innovation, Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, United Kingdom.
Chloe
C
Pass
Research, Development and Innovation, Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, United Kingdom.
Anne
A
Atkinson
Research, Development and Innovation, Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, United Kingdom.
Neil W A
NW
Mcgowan
Scottish National Blood Transfusion Service, Edinburgh Royal Infirmary, United Kingdom.
Lynn
L
Manson
Research, Development and Innovation, Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, United Kingdom; Scottish National Blood Transfusion Service, Edinburgh Royal Infirmary, United Kingdom.
Mark L
ML
Turner
Research, Development and Innovation, Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh, United Kingdom.
John D M
JD
Campbell
MRC Centre for Regenerative Medicine, Max Born Crescent, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: stuart.forbes@ed.ac.uk.
Stuart J
SJ
Forbes
D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D015331:Cohort Studies; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy; D008115:Liver Regeneration; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D008297:Male; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000473:pathology
D018925:Chemokines; D016207:Cytokines; D018950:Lipopolysaccharide Receptors