A
new has examined the expression of thousands of genes in stem cell
generated motor neurons that are known to die in patients with
amyotrophic lateral sclerosis, a fatal neurological disorder known as
ALS or Lou Gehrig's disease.
The study, published in the peer-reviewed journal Neuron,
revealed sex was one of the main drivers of different gene expression
in motor neurons, regardless of whether they were from patients
diagnosed with ALS.
“This is the first time that nearly 450 lines of stem cells have been
simultaneously differentiated and turned into motor neurons from
patients with ALS and healthy controls,” said a co-senior and
co-corresponding author of the study. “This was a collaborative effort
with incredibly hard-working teams of scientists across many
laboratories to provide a vital resource for the ALS community.”
The discovery is the first set of in-depth findings that stem from Answer ALS,
one of the largest resources for ALS biological samples in the world.
Answer ALS is part of a collaborative effort with over 100 scientists
that includes biological and clinical data from more than 1,000 ALS
patients.
The data is generated from patient stem cells that are then turned into
motor neurons, the nerve cells responsible for muscle function. These
motor neurons give researchers a better understanding of the mechanisms
of the fatal disease and can potentially help lead to the development
of new therapeutics that target specific cells and pathways.
While the approach of using human stem cells to model a disease isn’t
the first, no one has ever analyzed this many stem cell lines from
patients with ALS.
ALS is a complex disease that remains poorly understood with no known
cure. The disease causes damage to motor neurons in the brain and spinal
cord, leading to the loss of muscle control and ultimately movement.
Currently, there is no medical treatment that effectively targets the
fatal disease, other than measures—like respirators or feeding tubes—to
help patients be more comfortable.
To understand why ALS happens and identify distinct molecular signatures
of ALS in men and women, the team used 341 stem cell lines from ALS
patients, which were differentiated into motor neurons, along with 92
lines from a healthy control group.
The team performed and analyzed RNA sequencing that can measure the
expression of up to 32,000 genes in each sample. This gives the teams
the ability to detect gene patterns that may be affected by the disease
and to see if there were any signals that would separate ALS patients
from healthy controls.
Instead of finding prominent differences related to ALS, the team found
striking differences between males and females, regardless of whether
they were diagnosed with ALS. The investigators also were surprised to
find that the male ALS stem cells generated significantly more motor
neurons than the control group, but this was not observed with stem
cells from females.
“We hypothesized that we would see differences in gene expression
between ALS and healthy control groups, but the changes were subtle”
said a co-first author of the study. “However, when we analyzed males
and females separately, some specific changes in gene expression were
seen—particularly in male ALS samples.”
Previous studies using this approach have only used a few lines and
often not balanced their experiments for male and female subjects. Only
doing this at such a large scale revealed that sex was one of the main
drivers of different gene expression in motor neurons.
“It is known that women are less likely to get ALS than men, and if they
do get diagnosed with it, it’s generally a little later in life and
affects different sets of motor neurons,” said another author. “Now that
we have discovered gene expression patterns that can distinguish male
and female motor neurons, it may help with designing therapies in the
future.”
Investigators plan to continue analyzing the data that is continuously being collected and deposited into the Answer ALS online, open-source portal.
All of the data described in the resource paper is available for
scientists to download, and the stem cells are available through the
Cedars-Sinai iPSC Core.
“The take-home message is that these big data sets and large numbers of
ALS and control stem cell lines are now available to the ALS community
to use and look for new causes and treatments for this devastating
disease,” the author said.
https://www.cell.com/neuron/fulltext/S0896-6273(23)00034-X
http://sciencemission.com/site/index.php?page=news&type=view&id=protocols%2Flarge-scale-differentiat&filter=25
