EMBO Molecular Medicine,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 25, 2025
Abstract
Liver
fibrosis
is
a
major
cause
of
death
worldwide.
As
progressive
step
in
chronic
liver
disease,
almost
always
diagnosed
too
late
with
limited
treatment
options.
Here,
we
uncover
the
spatial
transcriptional
landscape
driving
human
using
single
nuclei
RNA
and
Assay
for
Transposase-Accessible
Chromatin
(ATAC)
sequencing
to
deconvolute
multi-cell
transcriptomic
profiling
cirrhosis.
Through
multi-modal
data
integration,
define
molecular
signatures
cell
state
transitions
disease
an
impaired
cellular
response
directional
trajectory
between
hepatocytes
cholangiocytes
associated
remodelling.
We
identify
pro-fibrogenic
non-parenchymal
subpopulations
co-localised
within
fibrotic
niche
localise
transitional
states
at
scar
interface.
This
combined
approach
provides
atlas
gene
regulation
defines
targeted
therapeutics
or
as
early
diagnostic
markers
disease.
Nature,
Journal Year:
2023,
Volume and Issue:
619(7970), P. 572 - 584
Published: July 19, 2023
Abstract
The
intestine
is
a
complex
organ
that
promotes
digestion,
extracts
nutrients,
participates
in
immune
surveillance,
maintains
critical
symbiotic
relationships
with
microbiota
and
affects
overall
health
1
.
intesting
has
length
of
over
nine
metres,
along
which
there
are
differences
structure
function
2
localization
individual
cell
types,
type
development
trajectories
detailed
transcriptional
programs
probably
drive
these
function.
Here,
to
better
understand
differences,
we
evaluated
the
organization
single
cells
using
multiplexed
imaging
single-nucleus
RNA
open
chromatin
assays
across
eight
different
intestinal
sites
from
donors.
Through
systematic
analyses,
find
compositions
differ
substantially
regions
demonstrate
complexity
epithelial
subtypes,
same
types
organized
into
distinct
neighbourhoods
communities,
highlighting
immunological
niches
present
intestine.
We
also
map
gene
regulatory
suggestive
differentiation
cascade,
associate
disease
heritability
specific
types.
These
results
describe
composition,
regulation
for
this
organ,
serve
as
an
important
reference
understanding
human
biology
disease.
Nature Biotechnology,
Journal Year:
2023,
Volume and Issue:
41(12), P. 1765 - 1775
Published: May 8, 2023
Abstract
Organoids
generated
from
human
pluripotent
stem
cells
provide
experimental
systems
to
study
development
and
disease,
but
quantitative
measurements
across
different
spatial
scales
molecular
modalities
are
lacking.
In
this
study,
we
multiplexed
protein
maps
over
a
retinal
organoid
time
course
primary
adult
tissue.
We
developed
toolkit
visualize
progenitor
neuron
location,
the
arrangements
of
extracellular
subcellular
components
global
patterning
in
each
addition,
single-cell
transcriptome
chromatin
accessibility
timecourse
dataset
inferred
gene
regulatory
network
underlying
development.
integrated
genomic
data
with
spatially
segmented
nuclei
into
multimodal
atlas
explore
ganglion
cell
(RGC)
neighborhoods,
highlighting
pathways
involved
RGC
death
showing
that
mosaic
genetic
perturbations
organoids
insight
fate
regulation.
Annual Review of Pathology Mechanisms of Disease,
Journal Year:
2024,
Volume and Issue:
19(1), P. 453 - 478
Published: Jan. 24, 2024
Acetaminophen
(APAP)
overdose
is
the
clinically
most
relevant
drug
hepatotoxicity
in
western
countries,
and,
because
of
translational
relevance
animal
models,
APAP
mechanistically
studied
drug.
This
review
covers
intracellular
signaling
events
starting
with
metabolism
and
central
role
mitochondrial
dysfunction
involving
oxidant
stress
peroxynitrite.
Mitochondria-derived
endonucleases
trigger
nuclear
DNA
fragmentation,
point
no
return
for
cell
death.
In
addition,
adaptive
mechanisms
that
limit
death
are
discussed
including
autophagy,
morphology
changes,
biogenesis.
Extensive
evidence
supports
oncotic
necrosis
as
mode
death;
however,
a
partial
overlap
apoptosis,
ferroptosis,
pyroptosis
basis
controversial
discussions.
Furthermore,
an
update
on
sterile
inflammation
injury
repair
activation
Kupffer
cells,
monocyte-derived
macrophages,
neutrophils
provided.
Understanding
these
led
to
discovery
N-acetylcysteine
recently
fomepizole
effective
antidotes
against
toxicity.
Nature,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 12, 2025
Abstract
Hepatic
stellate
cells
(HSCs)
have
a
central
pathogenetic
role
in
the
development
of
liver
fibrosis.
However,
their
fibrosis-independent
and
homeostatic
functions
remain
poorly
understood
1–5
.
Here
we
demonstrate
that
genetic
depletion
HSCs
changes
WNT
activity
zonation
hepatocytes,
leading
to
marked
alterations
regeneration,
cytochrome
P450
metabolism
injury.
We
identify
R-spondin
3
(RSPO3),
an
HSC-enriched
modulator
signalling,
as
responsible
for
these
hepatocyte-regulatory
effects
HSCs.
HSC-selective
deletion
Rspo3
phenocopies
HSC
on
hepatocyte
gene
expression,
zonation,
size,
regeneration
P450-mediated
detoxification,
exacerbates
alcohol-associated
metabolic
dysfunction-associated
steatotic
disease.
RSPO3
expression
decreases
with
activation
is
inversely
associated
outcomes
patients
These
protective
hepatocyte-regulating
via
resemble
R-spondin-expressing
stromal
niche
other
organs
should
be
integrated
into
current
therapeutic
concepts.
Biochemical Pharmacology,
Journal Year:
2024,
Volume and Issue:
228, P. 116056 - 116056
Published: Feb. 11, 2024
Liver
injury
and
acute
liver
failure
caused
by
an
acetaminophen
(APAP)
overdose
is
a
significant
clinical
problem
in
western
countries.
With
the
introduction
of
mouse
model
APAP
hepatotoxicity
1970
s,
fundamental
mechanisms
cell
death
were
discovered.
This
included
recognition
that
part
dose
metabolized
cytochrome
P450
generating
reactive
metabolite
detoxified
glutathione.
After
partial
depletion
glutathione,
will
covalently
bind
to
sulfhydryl
groups
proteins,
which
initiating
event
toxicity.
insight
led
N-acetyl-L-cysteine,
glutathione
precursor,
as
antidote
against
clinic.
Despite
substantial
progress
our
understanding
pathomechanisms
over
last
decades
viable
new
antidotes
only
emerged
recently.
review
discuss
background,
action,
prospects
existing
FDA-approved
N-acetylcysteine,
several
drug
candidates
under
development
[4-methylpyrazole
(fomepizole),
calmangafodipir]
examples
additional
therapeutic
targets
(Nrf2
activators)
regeneration
promoting
agents
(thrombopoietin
mimetics,
adenosine
A2B
receptor
agonists,
Wharton's
Jelly
mesenchymal
stem
cells).
Although
there
are
clear
limitations
certain
approaches,
reason
be
optimistic.
The
pathophysiology
consideration
drugs
for
recent
years.
Based
on
currently
available
information,
it
likely
this
result
could
used
adjunct
treatment
N-acetylcysteine.
Stem Cell Reports,
Journal Year:
2025,
Volume and Issue:
unknown, P. 102391 - 102391
Published: Jan. 1, 2025
During
gastrulation,
Wnt-β-catenin
signaling
dictates
lineage
bifurcation
generating
different
mesoderm
cell
types.
However,
the
specific
role
of
Wnt
receptors
in
specification
remains
elusive.
Using
selective
Frizzled
(FZD)
and
LRP5/6
antibody-based
agonists,
we
examined
FZD
receptors'
function
during
directed
differentiation
human
pluripotent
stem
cells
(hPSCs).
We
found
that
FZD2
FZD7
are
expressed
at
membrane
hPSCs
their
activation
triggers
β-catenin
with
kinetics,
thereby
influencing
patterning
choices.
Specifically,
enhances
both
paraxial
lateral
differentiation,
whereas
favors
mesoderm.
Mechanistically,
promotes
sustained
levels,
guiding
toward
mesoderm,
while
blocking
In
contrast,
kinetics
display
similar
initial
but
more
dampening
signaling,
permitting
induction
addition
to
specification.
Our
findings
reveal
non-redundant
roles
for
specification,
offering
leverage
precise
outcomes.
