bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2022,
Номер
unknown
Опубликована: Ноя. 15, 2022
Abstract
Background
The
complex
pathology
of
mild
traumatic
brain
injury
(mTBI)
is
a
main
contributor
to
the
difficulties
in
achieving
successful
therapeutic
regimen.
Thyroxine
(T4)
administration
has
been
shown
prevent
cognitive
impairments
induced
by
mTBI
mice.
Method
To
understand
underlying
mechanism,
we
carried
out
single
cell
transcriptomic
study
investigate
spatiotemporal
effects
T4
on
individual
types
hippocampus
and
frontal
cortex
at
three
post-injury
stages.
Findings
Our
multi-tissue
multi-stage
results
showed
that
treatment
altered
proportions
transcriptomes
numerous
across
tissues
timepoints,
particularly
oligodendrocytes,
astrocytes,
microglia,
which
are
crucial
for
repair.
also
reversed
expression
mTBI-affected
genes
such
as
Ttr,
mt-Rnr2
,
Ggn12,
Malat1,
Gnaq,
Myo3a
well
pathways
cell/energy/iron
metabolism,
immune
response,
nervous
system,
cytoskeleton-related
pathways.
Cell-type
specific
network
modeling
revealed
mitigated
select
mTBI-perturbed
dynamic
shifts
subnetworks
related
cycle,
stress
RNA
processing
oligodendrocytes.
Cross
cell-type
ligand-receptor
networks
recapitulated
roles
App,
Hmgb1,
Fn1,
Tnf
mTBI,
latter
two
ligands
having
previously
identified
TBI
hubs.
and/or
signature
were
enriched
human
genome-wide
association
(GWAS)
candidate
cognitive,
psychiatric
neurodegenerative
disorders
supporting
potential
treatment.
Interpretation
systems-level
approach
elucidated
temporal
spatial
reprogramming
genes,
pathways,
networks,
cell-cell
communications
through
mitigates
dysfunction
mTBI.
Funding
This
work
was
funded
NIHR01NS117148
X.Y.
F.G.P.
Research
Context
Evidence
before
this
Dysfunction
resulting
from
can
display
immediately
several
years
post-injury.
It
impacts
various
regions,
including
cortex,
linked
distinct
disease
pathologies.
complexity
molecular
dynamics
perturbation
caused
hinder
our
ability
establish
an
effective
approach.
Recently,
thyroid
hormone
poses
promise
target
based
previous
scRNA-seq
studies.
Yet,
mechanisms
alleviates
specifically
those
spatial,
temporal,
specificity,
remain
unexplored.
Added
value
We
examined
impact
intervention
mitigating
investigating
transcriptome
functional
affected
hippocampus,
different
stages
injury.
Utilizing
systems
biology
approach,
conducted
within-
between-cell-type
modeling,
communication
integrating
studies
analysis.
comprehensive
strategy
aimed
elucidate
cellular
averts
Implications
all
available
evidence
findings
offer
wide
range
biological
processes,
thereby
preventing
advancement
mTBI-induced
associated
diseases.
suggests
advantages
efficacy
compared
other
options
concentrate
targets.
Frontiers in Cellular Neuroscience,
Год журнала:
2024,
Номер
18
Опубликована: Фев. 28, 2024
Traumatic
brain
injury
(TBI)
is
one
of
the
most
common
pathological
conditions
impacting
central
nervous
system
(CNS).
A
neurological
deficit
associated
with
TBI
results
from
a
complex
pathogenetic
mechanisms
including
glutamate
excitotoxicity,
inflammation,
demyelination,
programmed
cell
death,
or
development
edema.
The
critical
components
contributing
to
CNS
response,
damage
control,
and
regeneration
after
are
glial
cells–in
reaction
tissue
damage,
their
activation,
hypertrophy,
proliferation
occur,
followed
by
formation
scar.
scar
creates
barrier
in
damaged
helps
protect
acute
phase
post-injury.
However,
this
process
prevents
complete
recovery
late/chronic
producing
permanent
scarring,
which
significantly
impacts
function.
Various
types
participate
formation,
but
mostly
attributed
reactive
astrocytes
microglia,
play
important
roles
several
pathologies.
Novel
technologies
whole-genome
transcriptomic
epigenomic
analyses,
unbiased
proteomics,
show
that
both
microglia
represent
groups
heterogenic
subpopulations
different
genomic
functional
characteristics,
responsible
for
role
neurodegeneration,
neuroprotection
regeneration.
Depending
on
representation
distinct
glia
subpopulations,
as
well
regenerative
processes
delayed
neurodegeneration
may
thus
differ
nearby
remote
areas
structures.
This
review
summarizes
process,
where
resultant
effect
severity-,
region-
time-dependent
determined
model
distance
explored
area
lesion
site.
Here,
we
also
discuss
findings
concerning
intercellular
signaling,
long-term
possibilities
novel
therapeutical
approaches.
We
believe
comprehensive
study
an
emphasis
cells,
involved
post-injury
processes,
be
helpful
further
research
decisive
factor
when
choosing
model.
Neuron,
Год журнала:
2024,
Номер
112(18), С. 3069 - 3088.e4
Опубликована: Июль 16, 2024
Traumatic
brain
injury
(TBI)
heterogeneity
remains
a
critical
barrier
to
translating
therapies.
Identifying
final
common
pathways/molecular
signatures
that
integrate
this
informs
biomarker
and
therapeutic-target
development.
We
present
the
first
large-scale
murine
single-cell
atlas
of
transcriptomic
response
TBI
(334,376
cells)
across
clinically
relevant
models,
sex,
region,
time
as
foundational
step
in
molecularly
deconstructing
heterogeneity.
Results
were
unique
cell
populations,
regions,
time,
highlighting
importance
cell-level
resolution.
identify
cell-specific
targets
previously
unrecognized
roles
for
microglial
ependymal
subtypes.
Ependymal-4
was
hub
neuroinflammatory
signaling.
A
distinct
lineage
shared
features
with
disease-associated
microglia
at
24
h,
persistent
gene-expression
changes
microglia-4
even
6
months
after
contusional
TBI,
contrasting
all
other
types
mostly
returned
naive
levels.
Regional
sexual
dimorphism
noted.
CEREBRI,
our
searchable
(https://shiny.crc.pitt.edu/cerebri/),
identifies
subtypes/molecular
is
leverageable
platform
future
efforts
diseases
overlapping
pathophysiology.
Abstract
Activating
autologous
stem
cells
after
the
implantation
of
biomaterials
is
an
important
process
to
initiate
bone
regeneration.
Although
several
studies
have
demonstrated
mechanism
biomaterial‐mediated
regeneration,
a
comprehensive
single‐cell
level
transcriptomic
map
revealing
influence
on
regulating
temporal
and
spatial
expression
patterns
mesenchymal
(MSCs)
still
lacking.
Herein,
osteoimmune
microenvironment
depicted
around
classical
collagen/nanohydroxyapatite‐based
repair
materials
via
combining
analysis
RNA
sequencing
transcriptomics.
A
group
functional
MSCs
with
high
matrix
Gla
protein
(
Mgp
)
identified,
which
may
serve
as
pioneer
subpopulation
involved
in
repair.
Remarkably,
these
high‐expressing
hi
MSCs)
exhibit
efficient
osteogenic
differentiation
potential
orchestrate
implanted
biomaterials,
rewiring
polarization
osteoclastic
macrophages
through
Mdk/Lrp1
ligand–receptor
pair.
The
inhibition
activates
pro‐inflammatory
programs
osteoclastogenesis.
Meanwhile,
multiple
immune‐cell
subsets
also
close
crosstalk
between
secreted
phosphoprotein
1
(SPP1)
signaling
pathway.
These
cellular
profiles
interactions
characterized
this
study
can
broaden
understanding
MSC
subpopulations
at
early
stage
regeneration
provide
basis
for
materials‐designed
strategies
that
target
modulation.
Cell Death Discovery,
Год журнала:
2025,
Номер
11(1)
Опубликована: Фев. 5, 2025
Abstract
Traumatic
brain
injury
(TBI)
is
one
of
the
leading
causes
disability
and
mortality,
which
was
classified
as
low-altitude
TBI
high-altitude
TBI.
A
large
amount
literature
shows
that
associated
with
more
severe
neurological
impairments
higher
mortality
rates
compared
to
TBI,
due
special
environment
hypoxia.
However,
role
hypoxia
in
pathogenesis
remains
unclear.
In
order
deeply
investigate
this
scientific
issue,
we
constructed
a
hypoxic
model
at
different
altitudes
used
animal
behavioral
assessments
(Modified
severity
score,
rotarod
test,
elevated
plus
maze
test)
well
histopathological
analyses
(brain
gross
specimens,
water
content,
Evans
blue
inducible
factor-1α,
Hematoxylin-Eosin
staining
ROS
detection)
reveal
its
underlying
principles
characteristics.
We
found
altitude,
TBI-induced
deficits
were
changes
significant.
Single-nuclear
RNA
sequencing
subsequently
employed
further
differential
gene
expression
profiles
significant
increase
ferroptosis
astrocytes
cases
those
Analyzing
transcription
factors
depth,
Bach1
plays
crucial
regulating
key
molecules
induce
following
Down-regulation
can
effectively
alleviate
mice.
conclusion,
may
significantly
enhance
aggravate
by
up-regulating
expression.
Our
study
provides
theoretical
foundation
for
understanding
mechanism
targeted
intervention
therapy.
CNS Neuroscience & Therapeutics,
Год журнала:
2023,
Номер
29(11), С. 3446 - 3459
Опубликована: Июнь 2, 2023
Traumatic
brain
injury
(TBI)
is
a
leading
cause
of
long-term
disability
in
young
adults
and
induces
complex
neuropathological
processes.
Cellular
autonomous
intercellular
changes
during
the
subacute
phase
contribute
substantially
to
neuropathology
TBI.
However,
underlying
mechanisms
remain
elusive.
In
this
study,
we
explored
dysregulated
cellular
signaling
TBI.Single-cell
RNA-sequencing
data
(GSE160763)
TBI
were
analyzed
explore
cell-cell
communication
Upregulated
neurotrophic
factor
was
validated
mouse
model
Primary
cell
cultures
lines
used
as
vitro
models
examine
potential
affecting
signaling.Single-cell
analysis
revealed
that
microglia
astrocytes
most
affected
cells
Cell-cell
demonstrated
mediated
by
non-canonical
factors
midkine
(MDK),
pleiotrophin
(PTN),
prosaposin
(PSAP)
microglia/astrocytes
upregulated
Time-course
profiling
showed
MDK,
PTN,
PSAP
expression
primarily
TBI,
major
source
MDK
PTN
after
studies
enhanced
activated
microglia.
Moreover,
promoted
proliferation
neural
progenitors
derived
from
human-induced
pluripotent
stem
(iPSCs)
neurite
growth
iPSC-derived
neurons,
whereas
exclusively
stimulated
growth.The
played
crucial
role
neuroregeneration.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease,
Год журнала:
2024,
Номер
1870(8), С. 167344 - 167344
Опубликована: Июль 14, 2024
The
complex
pathology
of
mild
traumatic
brain
injury
(mTBI)
is
a
main
contributor
to
the
difficulties
in
achieving
successful
therapeutic
regimen.
Thyroxine
(T4)
administration
has
been
shown
prevent
cognitive
impairments
induced
by
mTBI
mice
but
mechanism
poorly
understood.
To
understand
underlying
mechanism,
we
carried
out
single
cell
transcriptomic
study
investigate
spatiotemporal
effects
T4
on
individual
types
hippocampus
and
frontal
cortex
at
three
post-injury
stages
mouse
model
mTBI.
We
found
that
treatment
altered
proportions
transcriptomes
numerous
across
tissues
timepoints,
particularly
oligodendrocytes,
astrocytes,
microglia,
which
are
crucial
for
repair.
also
reversed
expression
mTBI-affected
genes
such
as
Ttr,
mt-Rnr2,
Ggn12,
Malat1,
Gnaq,
Myo3a,
well
pathways
cell/energy/iron
metabolism,
immune
response,
nervous
system,
cytoskeleton-related
pathways.
Cell-type
specific
network
modeling
revealed
mitigated
select
mTBI-perturbed
dynamic
shifts
subnetworks
related
cycle,
stress
RNA
processing
oligodendrocytes.
Cross
cell-type
ligand-receptor
networks
roles
App,
Hmgb1,
Fn1,
Tnf
mTBI,
with
latter
two
ligands
having
previously
identified
TBI
hubs.
and/or
signature
were
enriched
human
genome-wide
association
(GWAS)
candidate
cognitive,
psychiatric
neurodegenerative
disorders
Our
systems-level
analysis
elucidated
temporal
spatial
reprogramming
genes,
pathways,
networks,
cell-cell
communications
mechanisms
through
mitigates
dysfunction
Journal of Cerebral Blood Flow & Metabolism,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 9, 2024
Single-cell
RNA
sequencing
(scRNA-seq)
is
a
high-throughput
transcriptomic
approach
with
the
power
to
identify
rare
cells,
discover
new
cellular
subclusters,
and
describe
novel
genes.
scRNA-seq
can
simultaneously
reveal
dynamic
shifts
in
phenotypes
heterogeneities
subtypes.
Since
publication
of
first
protocol
on
2009,
this
evolving
technology
has
continued
improve,
through
use
cell-specific
barcodes,
adoption
droplet-based
systems,
development
advanced
computational
methods.
Despite
induction
stress
response
during
tissue
dissociation
process,
remains
popular
technology,
commercially
available
methods
have
been
applied
brain.
Recent
advances
spatial
transcriptomics
now
allow
researcher
capture
positional
context
transcriptional
activity,
strengthening
our
knowledge
organization
cell-cell
interactions
spatially
intact
tissues.
A
combination
data
proteomic,
metabolomic,
or
chromatin
accessibility
promising
direction
for
future
research.
Herein,
we
provide
an
overview
workflow,
analyses
methods,
pros
cons
technology.
We
also
summarize
latest
achievements
stroke
acute
traumatic
brain
injury,
applications
transcriptomics.
Annals of Medicine,
Год журнала:
2025,
Номер
57(1)
Опубликована: Янв. 20, 2025
Background
Pleiotrophin
(PTN),
a
secreted
multifunctional
growth
factor,
is
highly
expressed
in
the
developing
brain.
Recently,
many
studies
have
indicated
that
PTN
participates
development
of
brain
and
plays
neuroprotection
after
injury,
especially
promoting
neuronal
survival
neurite
outgrowth,
stimulating
oligodendrocyte
maturation
myelination,
modulating
neuroinflammation,
so
on.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Март 14, 2025
Astrocytes
are
closely
linked
to
depression,
and
the
prefrontal
cortex
(PFC)
is
an
important
brain
region
involved
in
major
depressive
disorder
(MDD).
However,
underlying
mechanism
by
which
astrocytes
within
PFC
contribute
MDD
remains
unclear.
Using
single-nucleus
RNA
sequencing
analyses,
we
show
a
significant
reduction
attenuated
pleiotrophin-protein
tyrosine
phosphatase
receptor
type
Z1
(PTN-PTPRZ1)
signaling
astrocyte-to-excitatory
neuron
communication
of
male
patients.
We
find
reduced
PTN
dorsomedial
mice
with
depression
induced
chronic
restraint
social
defeat
stress.
Knockdown
astrocytic
induces
depression-related
responses,
reversed
exogenous
supplementation
or
overexpression
PTN.
The
antidepressant
effects
exerted
require
interaction
PTPRZ1
excitatory
neurons,
PTN-PTPRZ1
activates
AKT
pathway
regulate
responses.
Our
findings
indicate
PTN-PTPRZ1-AKT
may
be
potential
therapeutic
target
for
MDD.
but
mechanisms
remain
Here,
authors
that
pleiotrophin
contributes
depression-like
phenotype
mice.
Journal of Neuroinflammation,
Год журнала:
2025,
Номер
22(1)
Опубликована: Апрель 18, 2025
Traumatic
brain
injury
(TBI)
initiates
a
cascade
of
cellular
and
molecular
events
that
promote
acute
long-term
patterns
neuronal,
glial,
vascular,
synaptic
vulnerability
leading
to
lasting
neurological
deficits.
These
complex
responses
lead
programmed
cell
death,
diffuse
axonal
injury,
increased
blood-brain
barrier
disruption,
neuroinflammation,
reactive
gliosis,
each
potential
target
for
therapeutic
interventions.
Posttraumatic
hypothermia
(TH)
has
been
reported
be
highly
protective
after
spinal
cord
studies
have
investigated
mechanisms
underlying
mild
hypothermic
protection
while
commonly
assessing
heterogenous
populations.
In
this
study
we
conducted
single-cell
RNA
sequencing
(scRNA-seq)
on
cerebral
cortical
tissues
experimental
TBI
followed
by
period
normothermia
or
comprehensively
assess
multiple
type-specific
transcriptional
responses.
C57BL/6
mice
underwent
moderate
controlled
impact
(CCI)
sham
surgery
then
placed
under
sustained
(37⁰C)
(33⁰C)
2
h.
After
24
h,
including
peri-contused
regions
were
processed
scRNA-seq.
Unbiased
clustering
revealed
heterogeneity
among
glial
immune
cells
at
subacute
posttraumatic
time
point.
The
analysis
also
vascular
subtypes
associated
with
neovascularization
debris
clearance,
respectively.
Compared
normothermic
conditions,
TH
treatment
altered
the
abundance
specific
induced
astrocyte-specific
modulation
neurotropic
factor
gene
expression.
addition,
an
increase
in
proportion
endothelial
tip
group
was
documented
compared
normothermia.
data
emphasize
importance
early
temperature-sensitive
processes
producing
potentially
neuroprotective
downstream
signaling
cascades
cell-type-dependent
manner.
use
scRNA-seq
address
treatments
provides
valuable
resource
identifying
targetable
biological
pathways
development
reparative