Neutrophils Derived from Genetically Modified Human Induced Pluripotent Stem Cells Circulate and Phagocytose Bacteria In Vivo

Stem Cells Translational Medicine
Lisa R TrumpJose A Cancelas

Abstract

Bacterial and fungal infections are a major cause of morbidity and mortality in neutropenic patients. Donor-derived neutrophil transfusions have been used for prophylaxis or treatment for infection in neutropenic patients. However, the short half-life and the limited availability of large numbers of donor-derived neutrophils for transfusion remain a significant hurdle in the implementation of neutrophil transfusion therapy. Here, we investigate the in vitro and in vivo activity of neutrophils generated from human induced pluripotent stem cells (iPSC), a potentially unlimited resource to produce neutrophils for transfusion. Phenotypic analysis of iPSC-derived neutrophils reveal reactive oxygen species production at similar or slightly higher than normal peripheral blood neutrophils, but have an ∼50%-70% reduced Escherichia coli phagocytosis and phorbol 12-myristate 13-acetate induced formation of neutrophil extracellular traps (NET). Signaling of granulocytic precursors identified impaired AKT activation, but not ERK or STAT3, in agonist-stimulated iPSC-derived neutrophils. Expression of a constitutively activated AKT in iPSC-derived neutrophils restores most phagocytic activity and NET formation. In a model of bacterial induced...Continue Reading

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Citations

May 19, 2019·Stem Cells Translational Medicine·Stuart P Atkinson
Jan 29, 2021·Journal of Inflammation Research·Marfa BlanterSofie Struyf
Apr 2, 2021·Cellular Microbiology·Enrica Pellegrino, Maximiliano G Gutierrez

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Methods Mentioned

BETA
myristoylation
fluorescence assisted cell sorting
flow cytometry
FACS
PMA
confocal microscopy
leukapheresis

Clinical Trials Mentioned

NCT01297543
NCT00891137
NCT02282215

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