GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18
PLoS Pathogens,
Год журнала:
2025,
Номер
21(2), С. e1012654 - e1012654
Опубликована: Фев. 3, 2025
Neutrophils
are
critical
for
host
defense
against
fungi.
However,
the
short
life
span
and
lack
of
genetic
tractability
primary
human
neutrophils
has
limited
in
vitro
analysis
neutrophil-fungal
interactions.
Human
induced
pluripotent
stem
cell
(iPSC)-derived
(iNeutrophils)
provide
a
genetically
tractable
system
to
study
responses
neutrophils.
Here,
we
show
that
deletion
transcription
factor
GATA1
from
iPSCs
results
iNeutrophils
with
improved
antifungal
activity
Aspergillus
fumigatus.
GATA1-knockout
(KO)
have
increased
maturation,
pattern
recognition
receptor
expression
neutrophil
effector
functions
compared
wild-type
iNeutrophils.
also
shift
their
metabolism
following
stimulation
fungal
β-glucan
pentose
phosphate
pathway
(PPP),
similar
Furthermore,
integrin
CD18
attenuates
ability
GATA1-KO
kill
A.
fumigatus
but
is
not
necessary
metabolic
shift.
Collectively,
these
findings
support
as
robust
immunity
identified
specific
roles
response.
Язык: Английский
Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 8, 2025
Abstract
Neutrophils
are
highly
abundant
innate
immune
cells
that
constantly
produced
from
myeloid
progenitors
in
the
bone
marrow.
Differentiated
neutrophils
can
perform
an
arsenal
of
effector
functions
critical
for
host
defense.
This
study
aims
to
quantitatively
understand
neutrophil
mitochondrial
metabolism
throughout
differentiation
and
activation,
elucidate
impact
on
functions.
To
metabolic
remodeling
differentiation,
murine
ER-Hoxb8
progenitor-derived
human
induced
pluripotent
stem
cell-derived
were
assessed
as
models.
upon
differentiated
primary
activated
with
various
stimuli,
including
ionomycin,
MSU
crystals,
PMA.
Characterization
cellular
by
isotopic
tracing,
extracellular
flux
analysis,
metabolomics,
fluorescence-lifetime
imaging
microscopy
revealed
dynamic
changes
metabolism.
As
mature,
decreases
drastically,
energy
production
is
fully
offloaded
oxidative
phosphorylation,
glucose
oxidation
through
TCA
cycle
substantially
reduced.
Nonetheless,
mature
retain
capacity
Upon
stimulation
certain
rapidly
activated.
Mitochondrial
pyruvate
carrier
inhibitors
reduce
this
re-activation
inhibit
release
traps.
also
impacts
redox
status,
migration,
apoptosis
without
significantly
changing
overall
bioenergetics.
Together,
these
results
demonstrate
dynamically
remodeled
plays
a
significant
role
function
fate.
Furthermore,
findings
point
therapeutic
potential
range
conditions
where
dysregulated
response
drives
inflammation
contributes
pathology.
Язык: Английский
Micro blood analysis technology (μBAT): multiplexed analysis of neutrophil phenotype and function from microliter whole blood samples
Lab on a Chip,
Год журнала:
2024,
Номер
24(17), С. 4198 - 4210
Опубликована: Янв. 1, 2024
There
is
an
ongoing
need
to
do
more
with
less
and
provide
highly
multiplexed
analysis
from
limited
sample
volumes.
Improved
"sample
sparing"
assays
would
have
a
broad
impact
across
pediatric
other
rare
type
studies
in
addition
enabling
sequential
sampling.
This
capability
advance
both
clinical
basic
research
applications.
Here
we
report
the
micro
blood
technology
(μBAT),
microfluidic
platform
that
supports
of
neutrophils
single
drop
blood.
We
demonstrate
orthogonal
capabilities
μBAT
including
functional
(phagocytosis,
neutrophil
extracellular
traps,
optical
metabolic
imaging)
molecular
(gene
expression,
cytokine
secretion).
Importantly
validate
our
microscale
using
macroscale
benchmark
assay.
compatible
lancet
puncture
or
microdraw
devices,
its
design
facilitates
rapid
operations
without
for
specialized
equipment.
offers
new
method
investigating
function
populations
restricted
amounts.
Язык: Английский
GATA1-deficient human pluripotent stem cells generate neutrophils with improved antifungal immunity that is mediated by the integrin CD18
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 11, 2024
Abstract
Neutrophils
are
critical
for
host
defense
against
fungi.
However,
the
short
life
span
and
lack
of
genetic
tractability
primary
human
neutrophils
has
limited
in
vitro
analysis
neutrophil-fungal
interactions.
Human
induced
pluripotent
stem
cell
(iPSC)-derived
(iNeutrophils)
a
genetically
tractable
alternative
to
neutrophils.
Here,
we
show
that
deletion
transcription
factor
GATA1
from
iPSCs
results
iNeutrophils
with
improved
antifungal
activity
Aspergillus
fumigatus
.
knockout
(KO)
have
increased
maturation,
pattern
recognition
receptor
expression
more
readily
execute
neutrophil
effector
functions
compared
wild-type
iNeutrophils.
also
shift
their
metabolism
following
stimulation
fungal
β-glucan,
including
an
upregulation
pentose
phosphate
pathway
(PPP),
similar
Furthermore,
integrin
CD18
attenuates
ability
GATA1-KO
kill
A.
but
is
not
necessary
PPP.
Collectively,
these
findings
support
as
robust
system
study
immunity
identified
specific
roles
response.
Author
Summary
important
first
responders
infections,
understanding
essential
better
elucidating
disease
dynamics.
Primary
lived
do
permit
manipulation,
limiting
use
interactions
analyses.
In
this
report
GATA1-deficient
generate
mature
than
display
pathogen
We
receptors
cells
at
levels
comparable
Deletion
blocks
control
growth
,
demonstrating
role
iNeutrophil
activity.
model
immunity.
Язык: Английский