ABSTRACT
Multiple
sclerosis
(MS)
is
the
most
prevalent
human
inflammatory
disease
of
central
nervous
system
with
demyelination
and
glial
scar
formation
as
pathological
hallmarks.
Glial
cells
are
key
drivers
lesion
progression
in
MS
roles
both
tissue
damage
repair
depending
on
surrounding
microenvironment
functional
state
individual
subtype.
In
this
review,
we
describe
recent
developments
context
cell
diversity
summarizing
findings
respect
to
maladaptive
functions
related
disease‐associated
subtypes.
A
particular
focus
spatial
temporal
dynamics
including
subtypes
microglia,
oligodendrocytes,
astrocytes.
We
contextualize
high‐dimensional
suggesting
that
dynamically
change
epigenomic,
transcriptomic,
metabolic
features
across
inflamed
rim
during
lesions.
summary,
detailed
knowledge
spatially
restricted
subtype
critical
for
a
better
understanding
pathology
its
pathogenesis
well
development
novel
therapies
targeting
specific
types.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 28, 2024
Abstract
The
ability
to
spatially
map
multiple
layers
of
the
omics
information
over
different
time
points
allows
for
exploring
mechanisms
driving
brain
development,
differentiation,
arealization,
and
alterations
in
disease.
Herein
we
developed
applied
spatial
tri-omic
sequencing
technologies,
DBiT
ARP-seq
(spatial
ATAC–RNA–Protein-seq)
CTRP-seq
CUT&Tag–
RNA–Protein-seq)
together
with
multiplexed
immunofluorescence
imaging
(CODEX)
dynamic
remodeling
development
neuroinflammation.
A
spatiotemporal
atlas
mouse
was
obtained
at
stages
from
postnatal
day
P0
P21,
compared
regions
interest
human
developing
brains.
Specifically,
cortical
area,
discovered
temporal
persistence
spreading
chromatin
accessibility
layer-defining
transcription
factors.
In
corpus
callosum,
observed
priming
myelin
genes
across
subregions.
Together,
it
suggests
a
role
layer
specific
projection
neurons
coordinate
axonogenesis
myelination.
We
further
mapped
lysolecithin
(LPC)
neuroinflammation
model
common
molecular
programs
Microglia,
exhibiting
both
conserved
distinct
inflammation
resolution,
are
transiently
activated
not
only
core
LPC
lesion,
but
also
distal
locations
presumably
through
neuronal
circuitry.
Thus,
this
work
unveiled
differential
neuroinflammation,
resulting
valuable
data
resource
investigate
function
Inferring
cellular
and
molecular
dynamics
of
multiple
sclerosis
(MS)
lesions
from
postmortem
tissue
collected
decades
after
onset
is
challenging.
Using
magnetic
resonance
image
(MRI)-guided
spatiotemporal
RNA
profiling
in
marmoset
experimental
autoimmune
encephalitis
(EAE),
we
mapped
lesion
modeled
perturbations
relevant
to
MS.
Five
distinct
microenvironments
emerged,
involving
neuroglial
responses,
destruction
repair,
brain
border
regulation.
Before
demyelination,
MRI
identified
a
high
ratio
proton
density-weighted
signal
T1
relaxation
time,
capturing
early
hypercellularity,
elevated
astrocytic
ependymal
senescence
signals
marked
perivascular
periventricular
areas
that
later
became
demyelination
hotspots.
As
expanded,
concentric
glial
barriers
formed,
initially
dominated
by
proliferating
diversifying
microglia
oligodendrocyte
precursors,
replaced
monocytes
lymphocytes.
We
highlight
SERPINE1+
astrocytes
as
signaling
hub
underlying
both
EAE
Frontiers in Immunology,
Год журнала:
2025,
Номер
15
Опубликована: Янв. 14, 2025
Introduction
Remyelination
of
demyelinated
axons
can
occur
as
an
endogenous
repair
mechanism
in
multiple
sclerosis
(MS),
but
its
efficacy
varies
between
both
MS
individuals
and
lesions.
The
molecular
cellular
mechanisms
that
drive
remyelination
remain
poorly
understood.
Here,
we
studied
the
relation
microglia
activation
activity
MS.
Methods
We
correlated
regenerative
(CD163
+
)
inflammatory
(iNOS
with
BCAS1
oligodendrocytes,
subdivided
into
early-stage
(<3
processes)
late-stage
(≥3
cells
brain
donors
high
or
low
remyelinating
potential
remyelinated
lesions
active
ramified/amoeboid
(non-foamy)
foamy
microglia.
A
cohort
categorized
efficiently
(ERDs;
n=25)
(PRDs;
n=17)
was
included,
based
on
their
proportion
at
autopsy.
Results
discussion
hypothesized
more
CD163
oligodendrocytes
non-foamy
from
ERDs
iNOS
fewer
PRDs.
For
microglia,
however,
no
differences
were
observed
donor
groups.
In
line
our
hypothesis,
found
INOS
significantly
increased
PRDs
compared
to
within
lesions,
detected
comparison
Although
for
did
find
vs
Interestingly,
a
positive
correlation
identified
presence
oligodendrocytes.
These
findings
suggest
impaired
maturation
encountering
may
underlie
deficits
unsuccessful
lesion
Abstract
The
Xenium
In
Situ
platform
is
a
new
spatial
transcriptomics
product
commercialized
by
10x
Genomics,
capable
of
mapping
hundreds
genes
in
situ
at
subcellular
resolution.
Given
the
multitude
commercially
available
technologies,
recommendations
choice
and
analysis
guidelines
are
increasingly
important.
Herein,
we
explore
25
datasets
generated
from
multiple
tissues
species,
comparing
scalability,
resolution,
data
quality,
capacities
limitations
with
eight
other
spatially
resolved
technologies
commercial
platforms.
addition,
benchmark
performance
open-source
computational
tools,
when
applied
to
datasets,
tasks
including
preprocessing,
cell
segmentation,
selection
variable
features
domain
identification.
This
study
serves
as
an
independent
Xenium,
provides
best
practices
for
such
datasets.
Amyotrophic
lateral
sclerosis
(ALS)
is
a
progressive
neurodegenerative
disease
characterized
by
motor
neuron
loss.
Microglia
and
astrocyte-driven
neuroinflammation
prominent
in
ALS,
but
the
cell
state
dynamics
pathways
driving
remain
unclear.
We
performed
single-nucleus
RNA
sequencing
of
ALS
spinal
cords
identified
altered
glial
states,
including
increased
expression
inflammatory
activation
markers.
Many
these
signals
converged
on
inflammation
death
regulator
receptor-interacting
protein
kinase
1
(RIPK1)
necroptotic
pathway.
In
superoxide
dismutase
(SOD1)G93A
mice,
blocking
RIPK1
activity
delayed
symptom
onset
impairment
modulated
responses.
used
human
induced
pluripotent
stem
(iPSC)-derived
neuron,
astrocyte,
microglia
tri-cultures
to
identify
potential
biomarkers
that
are
secreted
upon
vitro
inhibition
cerebrospinal
fluid
(CSF)
people
with
ALS.
These
data
reveal
ALS-enriched
populations
associated
suggest
deleterious
role
for
neuroinflammatory
signaling
pathogenesis.
Old
age
is
associated
with
a
decline
in
cognitive
function
and
an
increase
neurodegenerative
disease
risk1.
Brain
ageing
complex
accompanied
by
many
cellular
changes2.
Furthermore,
the
influence
that
aged
cells
have
on
neighbouring
how
this
contributes
to
tissue
unknown.
More
generally,
tools
systematically
address
question
tissues
not
yet
been
developed.
Here
we
generate
spatially
resolved
single-cell
transcriptomics
brain
atlas
of
4.2
million
from
20
distinct
ages
across
adult
lifespan
two
rejuvenating
interventions—exercise
partial
reprogramming.
We
build
spatial
clocks,
machine
learning
models
trained
atlas,
identify
cell-type-specific
transcriptomic
fingerprints
ageing,
rejuvenation
disease,
including
for
rare
cell
types.
Using
clocks
deep
learning,
find
T
cells,
which
increasingly
infiltrate
age,
marked
pro-ageing
proximity
effect
cells.
Surprisingly,
neural
stem
strong
pro-rejuvenating
also
potential
mediators
their
neighbours.
These
results
suggest
types
can
potent
neighbours
could
be
targeted
counter
ageing.
Spatial
represent
useful
tool
studying
cell–cell
interactions
contexts
should
allow
scalable
assessment
efficacy
interventions
disease.
A
map
mouse
at
different
reveals
signatures
effects
Spatial
transcriptomics
(ST)
represents
a
revolutionary
approach
in
molecular
biology,
providing
unprecedented
insights
into
the
spatial
organization
of
gene
expression
within
tissues.
This
review
aims
to
elucidate
advancements
ST
technologies,
their
computational
tools,
and
pivotal
applications
neuroscience.
It
is
begun
with
historical
overview,
tracing
evolution
from
early
image-based
techniques
contemporary
sequence-based
methods.
Subsequently,
methods
essential
for
data
analysis,
including
preprocessing,
cell
type
annotation,
clustering,
detection
spatially
variable
genes,
cell-cell
interaction
3D
multi-slices
integration
are
discussed.
The
central
focus
this
application
neuroscience,
where
it
has
significantly
contributed
understanding
brain's
complexity.
Through
ST,
researchers
advance
brain
atlas
projects,
gain
development,
explore
neuroimmune
dysfunctions,
particularly
tumors.
Additionally,
enhances
neuronal
vulnerability
neurodegenerative
diseases
like
Alzheimer's
neuropsychiatric
disorders
such
as
schizophrenia.
In
conclusion,
while
already
profoundly
impacted
challenges
remain
issues
enhancing
sequencing
technologies
developing
robust
tools.
underscores
transformative
potential
paving
way
new
therapeutic
research.