Journal of Clinical Investigation,
Год журнала:
2023,
Номер
133(22)
Опубликована: Сен. 28, 2023
Idiopathic
Pulmonary
Fibrosis
(IPF)
is
a
progressive
scarring
disease
arising
from
impaired
regeneration
of
the
alveolar
epithelium
after
injury.
During
regeneration,
type
2
epithelial
cells
(AEC2s)
assume
transitional
state
that
upregulates
multiple
keratins,
and
ultimately
differentiate
into
AEC1s.
In
IPF,
AECs
accumulate
with
ineffectual
AEC1
differentiation.
However,
whether
how
cause
fibrosis,
keratins
regulate
cell
accumulation
why
fibrosis
resolve
in
mouse
models
but
IPF
are
unclear.
Here,
we
show
human
keratin
(KRT)
8
genetic
variants
associated
IPF.
Krt8-/-
mice
protected
state.
Keratin
(K)
regulates
expression
macrophage
chemokines
recruitment.
Profibrotic
macrophages
myofibroblasts
promote
AECs,
establishing
K8-dependent
positive
feedback
loop
driving
fibrogenesis.
Finally,
rare
murine
highly
senescent,
basaloid,
do
not
AEC1s,
recapitulating
aberrant
basaloid
We
conclude
induce
maintained
by
manner;
mice,
most
resolve,
whereas
evolve
an
which
persists
fibrosis.
Cell,
Год журнала:
2023,
Номер
186(26), С. 5876 - 5891.e20
Опубликована: Дек. 1, 2023
Harmonizing
cell
types
across
the
single-cell
community
and
assembling
them
into
a
common
framework
is
central
to
building
standardized
Human
Cell
Atlas.
Here,
we
present
CellHint,
predictive
clustering
tree-based
tool
resolve
cell-type
differences
in
annotation
resolution
technical
biases
datasets.
CellHint
accurately
quantifies
cell-cell
transcriptomic
similarities
places
relationship
graph
that
hierarchically
defines
shared
unique
subtypes.
Application
multiple
immune
datasets
recapitulates
expert-curated
annotations.
also
reveals
underexplored
relationships
between
healthy
diseased
lung
states
eight
diseases.
Furthermore,
workflow
for
fast
cross-dataset
integration
guided
by
harmonized
hierarchy,
which
uncovers
underappreciated
adult
human
hippocampus.
Finally,
apply
12
tissues
from
38
datasets,
providing
deeply
curated
cross-tissue
database
with
∼3.7
million
cells
various
machine
learning
models
automatic
tissues.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Июль 29, 2023
Abstract
Accurate
cell
type
identification
is
a
key
and
rate-limiting
step
in
single-cell
data
analysis.
Single-cell
references
with
comprehensive
types,
reproducible
functionally
validated
identities,
common
nomenclatures
are
much
needed
by
the
research
community
for
automated
annotation,
integration,
sharing.
Here,
we
develop
computational
pipeline
utilizing
LungMAP
CellCards
as
dictionary
to
consolidate
transcriptomic
datasets
of
104
human
lungs
17
mouse
lung
samples
construct
reference
(CellRef)
both
normal
lungs.
CellRefs
define
48
40
types
catalogued
from
diverse
anatomic
locations
developmental
time
points.
We
demonstrate
accuracy
stability
their
utility
annotation
diseased
using
multiple
independent
methods
testing
data.
user-friendly
web
interfaces
easy
access
maximal
utilization
CellRefs.
Nature,
Год журнала:
2023,
Номер
620(7975), С. 890 - 897
Опубликована: Авг. 9, 2023
Abstract
Alveolar
epithelial
type
1
(AT1)
cells
are
necessary
to
transfer
oxygen
and
carbon
dioxide
between
the
blood
air.
2
(AT2)
serve
as
a
partially
committed
stem
cell
population,
producing
AT1
during
postnatal
alveolar
development
repair
after
influenza
A
SARS-CoV-2
pneumonia
1–6
.
Little
is
known
about
metabolic
regulation
of
fate
lung
cells.
Here
we
report
that
deleting
mitochondrial
electron
transport
chain
complex
I
subunit
Ndufs2
in
mouse
gestation
led
death
development.
Affected
mice
displayed
hypertrophic
with
AT2
features,
transitional
Mammalian
I,
comprising
45
subunits,
regenerates
NAD
+
pumps
protons.
Conditional
expression
yeast
NADH
dehydrogenase
(NDI1)
protein
without
proton
pumping
7,8
was
sufficient
correct
abnormal
avert
lethality.
Single-cell
RNA
sequencing
revealed
enrichment
integrated
stress
response
(ISR)
genes
Administering
an
ISR
inhibitor
9,10
or
precursor
reduced
gene
signatures
rescued
lethality
absence
function.
Notably,
epithelial-specific
loss
II
Sdhd
,
which
maintains
regeneration,
did
not
trigger
high
activation
These
findings
highlight
unanticipated
requirement
for
I-dependent
regeneration
directing
by
preventing
pathological
induction.
Journal of Clinical Investigation,
Год журнала:
2023,
Номер
133(22)
Опубликована: Сен. 28, 2023
Idiopathic
Pulmonary
Fibrosis
(IPF)
is
a
progressive
scarring
disease
arising
from
impaired
regeneration
of
the
alveolar
epithelium
after
injury.
During
regeneration,
type
2
epithelial
cells
(AEC2s)
assume
transitional
state
that
upregulates
multiple
keratins,
and
ultimately
differentiate
into
AEC1s.
In
IPF,
AECs
accumulate
with
ineffectual
AEC1
differentiation.
However,
whether
how
cause
fibrosis,
keratins
regulate
cell
accumulation
why
fibrosis
resolve
in
mouse
models
but
IPF
are
unclear.
Here,
we
show
human
keratin
(KRT)
8
genetic
variants
associated
IPF.
Krt8-/-
mice
protected
state.
Keratin
(K)
regulates
expression
macrophage
chemokines
recruitment.
Profibrotic
macrophages
myofibroblasts
promote
AECs,
establishing
K8-dependent
positive
feedback
loop
driving
fibrogenesis.
Finally,
rare
murine
highly
senescent,
basaloid,
do
not
AEC1s,
recapitulating
aberrant
basaloid
We
conclude
induce
maintained
by
manner;
mice,
most
resolve,
whereas
evolve
an
which
persists
fibrosis.
