Abstract
Regenerative
responses
are
particularly
important
in
the
lungs,
which
critical
for
gas
exchange
and
frequently
challenged
by
environmental
insults.
The
lung
progenitor
cells
play
a
central
role
regeneration
response,
their
dysfunction
is
associated
with
various
diseases.
Understanding
mechanisms
regulating
cell
function
essential
developing
new
therapeutic
approaches
to
promote
regeneration.
This
review
summarizes
recent
advancements
field
of
regeneration,
focusing
on
metabolic
control
function.
We
discuss
lineage
plasticity
cell–cell
signaling
under
different
physiological
conditions.
Additionally,
we
highlight
connection
between
diseases,
emphasizing
need
develop
strategies
regenerative
medicine
improve
capacity.
The EMBO Journal,
Год журнала:
2025,
Номер
44(3), С. 639 - 664
Опубликована: Янв. 15, 2025
Alveolar
type
2
(AT2)
cells
maintain
lung
health
by
acting
as
stem
and
producing
pulmonary
surfactant.
AT2
dysfunction
underlies
many
diseases,
including
interstitial
disease
(ILD),
in
which
some
inherited
forms
result
from
the
mislocalization
of
surfactant
protein
C
(SFTPC)
variants.
Lung
modeling
dissection
underlying
mechanisms
remain
challenging
due
to
complexities
deriving
maintaining
human
ex
vivo.
Here,
we
describe
development
mature,
expandable
organoids
derived
fetal
lungs
are
phenotypically
stable,
can
differentiate
into
AT1-like
cells,
genetically
manipulable.
We
use
these
test
key
effectors
SFTPC
maturation
identified
a
forward
genetic
screen
E3
ligase
ITCH,
demonstrating
that
their
depletion
phenocopies
pathological
redistribution
seen
for
SFTPC-I73T
variant.
In
summary,
demonstrate
novel
alveolar
organoid
model
it
identify
necessary
health.
Cell Communication and Signaling,
Год журнала:
2024,
Номер
22(1)
Опубликована: Май 27, 2024
Abstract
A
cell
is
a
dynamic
system
in
which
various
processes
occur
simultaneously.
In
particular,
intra-
and
intercellular
signaling
pathway
crosstalk
has
significant
impact
on
cell’s
life
cycle,
differentiation,
proliferation,
growth,
regeneration,
and,
consequently,
the
normal
functioning
of
an
entire
organ.
Hippo
YAP/TAZ
nucleocytoplasmic
shuttling
play
pivotal
role
development,
homeostasis,
tissue
particularly
lung
cells.
Intersignaling
communication
core
components
localization.
This
review
describes
between
key
pathways
(WNT,
SHH,
TGFβ,
Notch,
Rho,
mTOR)
using
cells
as
example
highlights
remaining
unanswered
questions.
Stem Cell Reports,
Год журнала:
2024,
Номер
19(4), С. 529 - 544
Опубликована: Март 28, 2024
Alveolar
type
2
(AT2)
epithelial
cells
are
tissue
stem
capable
of
differentiating
into
alveolar
1
(AT1)
for
injury
repair
and
maintenance
lung
homeostasis.
However,
the
factors
involved
in
human
AT2-to-AT1
cell
differentiation
not
fully
understood.
Here,
we
established
SFTPCGFP
AGERmCherry-HiBiT
dual-reporter
induced
pluripotent
(iPSCs),
which
detected
with
high
sensitivity
identified
inducing
AT1
from
AT2
their
progenitor
cells.
We
also
an
"on-gel"
spheroid
culture
suitable
medium-throughput
screening.
Among
274
chemical
compounds,
several
single
including
LATS-IN-1,
converted
Moreover,
YAP/TAZ
signaling
activation
AKT
suppression
synergistically
recapitulated
induction
transcriptomic,
morphological,
functionally
mature
Our
findings
provide
novel
insights
development
regenerative
medicine.
British Journal of Pharmacology,
Год журнала:
2024,
Номер
181(23), С. 4766 - 4781
Опубликована: Авг. 25, 2024
Background
and
Purpose
The
PDE4
family
is
considered
a
prime
target
for
therapeutic
intervention
in
several
fibro‐inflammatory
diseases.
We
have
investigated
the
molecular
mechanisms
of
nerandomilast
(BI
1015550),
preferential
PDE4B
inhibitor.
Experimental
Approach
In
addition
to
clinically
relevant
parameters
idiopathic
pulmonary
fibrosis
(IPF;
lung
function
measurement/high‐resolution
computed
tomography
scan/AI‐Ashcroft
score),
whole‐lung
homogenates
from
male
Wistar
rat
model
were
analysed
by
next‐generation
sequencing
(NGS).
Data
matched
with
public
domain
data
derived
human
IPF
samples
investigate
how
well
reflected
IPF.
scored
top
counter‐regulated
genes
following
treatment
single
cells
validated
disease
markers
discovered
using
disease‐relevant
vitro
assay
Key
Results
Nerandomilast
improved
decline
bleomycin‐treated
animals.
NGS
study,
most
transcripts
deregulated
bleomycin
normalised
treatment.
Most
notably,
significant
number
that
identified
also
found
animal
reversed
nerandomilast.
Mapping
single‐cell
revealed
strongest
effects
on
mesenchymal,
epithelial
endothelial
cell
populations.
primary
culture
system,
disease‐related
(bio)markers
inhibited
concentration‐dependent
manner.
Conclusions
Implications
This
study
further
supports
available
knowledge
about
anti‐inflammatory/antifibrotic
provides
novel
insights
into
mode
action
signalling
pathways
influenced
fibrosis.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 13, 2025
Abstract
Extracellular
matrix
(ECM)
stiffness
plays
a
crucial
role
in
regulating
cell
fate
and
maturation,
but
its
influence
on
lung
development
is
limited
known.
Here
we
utilized
stiffness-tunable
gelatin
methacryloyl
(GelMA)
hydrogels
to
investigate
how
ECM
influences
site-specific
stem
cell-derived
organoid
model.
We
found
increased
promoted
NKX2-1+
progenitor
cells
(LPCs)
generation.
In
airway
organoids
(hAWOs),
stiff
directed
proximal
differentiation
enriched
with
goblet,
ciliated,
basal
cells;
whereas
the
decreased
favored
emergence
of
secretory
proximal-distal
transition
zone
distal
airway.
alveolar
(hALOs),
enhanced
AT2
AT1
transition.
Moreover,
infection
assays
Omicron
BA.1.1
Delta
variants
recapitulated
proximal-to-distal
tropism
SARS-CoV-2
lung.
Transcriptomic
sequencing
revealed
regulates
via
Hippo,
TGF-β,
HIF
Wnt
pathways.
These
findings
advance
mechanism
understanding
provide
novel
mechanical
regulation
for
generating
organoids.
Abstract
Pulmonary
fibrosis
(PF)
is
a
chronic
and
progressive
interstitial
lung
disease
characterized
by
abnormal
activation
of
myofibroblasts
pathological
remodeling
the
extracellular
matrix,
with
poor
prognosis
limited
treatment
options.
Lung
transplantation
currently
only
approach
that
can
extend
life
expectancy
patients;
however,
its
applicability
severely
restricted
due
to
donor
shortages
patient‐specific
limitations.
Therefore,
search
for
novel
therapeutic
strategies
imperative.
In
recent
years,
stem
cells
have
shown
great
promise
in
field
regenerative
medicine
their
self‐renewal
capacity
multidirectional
differentiation
potential,
growing
body
literature
supports
efficacy
cell
therapy
PF
treatment.
This
paper
systematically
summarizes
research
progress
various
types
PF.
Furthermore,
it
discusses
primary
methods
clinical
outcomes
PF,
based
on
both
preclinical
data.
Finally,
current
challenges
key
factors
consider
are
objectively
analyzed,
future
directions
improving
this
proposed,
providing
new
insights
references
patients.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 31, 2025
Abstract
Chronic
obstructive
pulmonary
disease
is
characterized
by
inflammation
and
emphysema,
leading
to
progressive
alveolar
destruction.
Currently,
no
therapies
effectively
regenerate
the
epithelium.
Here,
we
describe
a
feeder-
serum-free
primary
adult
human
organoid
model
investigate
how
influences
regeneration.
We
achieve
long-term
expansion
of
multipotent
progenitor-like
cells,
while
an
type
2
(AT2)
maturation
protocol
enhances
surfactant
production
supports
tubular
myelin
formation.
Introducing
LATS
inhibitor
condition
induces
1
(AT1)
differentiation
maintaining
AT2
cells.
Using
this
platform,
find
that
interferon-gamma
exerts
cytotoxic
effects
on
AT1
cells
promoting
growth
regenerating
illustrating
single
inflammatory
stimulus
can
have
divergent
epithelial
cell
types.
These
findings
underscore
nuanced
influence
pro-inflammatory
cytokines
Our
provides
reductionist
platform
for
mechanistic
studies,
aimed
identify
strategies
enhance
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 17, 2025
Abstract
Idiopathic
pulmonary
fibrosis
(IPF)
is
a
progressive
and
incurable
lung
disease
characterized
by
tissue
scarring
that
disrupts
gas
exchange.
Epithelial
cell
dysfunction,
fibroblast
activation,
excessive
extracellular
matrix
deposition
drive
this
pathology
ultimately
leads
to
respiratory
failure.
Mechanistic
studies
have
shown
repeated
injury
alveolar
epithelial
cells
initiates
an
aberrant
wound-healing
response
in
surrounding
fibroblasts
through
secretion
of
mediators
like
transforming
growth
factor-β,
yet
the
precise
biological
pathways
contributing
progression
are
not
fully
understood.
To
better
study
these
interactions
there
critical
need
for
models
replicate
cellular
heterogeneity,
geometry,
biomechanics
distal
microenvironment.
In
study,
induced
pluripotent
stem
cell-derived
type
II
(iATII)
human
were
arranged
micro-architecture
embedded
soft
or
stiff
poly(ethylene
glycol)
norbornene
(PEG-NB)
hydrogels
recapitulated
mechanical
properties
healthy
fibrotic
tissue,
respectively.
The
co-cultured
then
exposed
pro-fibrotic
biochemical
cues,
including
inflammatory
cytokines
factors.
iATIIs
exhibited
differentiation
gene
expression
patterns
consistent
with
trends
observed
during
IPF
vivo
.
A
design
experiments
statistical
analysis
identified
combined
cue
exposure
as
most
effective
condition
modeling
vitro
Finally,
treatment
Nintedanib,
one
only
two
Food
Drug
Administration
(FDA)-approved
drugs
IPF,
was
assessed.
Treatment
reduced
indicated
downregulation
key
activation
genes,
upregulated
several
genes.
These
findings
demonstrate
3D
co-culture
hold
tremendous
potential
advancing
our
understanding
identifying
novel
therapeutic
targets.
Statement
significance
This
leverages
advanced
biomaterials
biofabrication
techniques
engineer
physiologically
relevant,
patient-specific,
sex-matched
fibrosis,
addressing
pre-clinical
drug
screening
platforms.
successfully
replicated
features
tissue.
Tuning
microenvironmental
stiffness
PEG-NB
match
values
exposing
iATII
pro-inflammatory
cues
recreated
hallmark
characteristics
pathogenesis,
loss,
well
activation.
utility
further
validated
demonstrating
responsiveness
clinically
available
IPF.
highlight
transformative
well-defined
biomaterial-based
elucidating
complex
mechanisms
accelerating
discovery
chronic
diseases
idiopathic
fibrosis.
Graphical
abstract
