Summary: Neurons derived from stem cells from veterans with PTSD respond differently to stress hormones than those derived from veterans without PTSD. The findings shed new light on how genetics can cause some to develop PTSD following a traumatic event.
Source: Mount Sinai Hospital
Neurons derived from stem cells from veterans with post-traumatic stress disorder (PTSD) respond differently to a stress hormone than those from veterans without PTSD, a finding that could provide insight into how genetics can make a person more likely to develop PTSD after exposure to trauma.
The study, published on October 20 in Natural neuroscience, is the first to use induced pluripotent stem cell models to study PTSD. It was conducted by a team of scientists from the Icahn School of Medicine at Mount Sinai, the James J. Peters Veterans Affairs Medical Center, the Yale School of Medicine and the New York Stem Cell Foundation Research Institute (NYSCF).
Post-traumatic stress disorder can develop following severe trauma and is a huge public health concern for veterans and civilians. However, the extent to which genetic and environmental factors contribute to individual clinical outcomes remains unknown.
To fill this information gap, the research team studied a cohort of 39 veterans with and without PTSD who were recruited from the James J Peters Veterans Affairs Medical Center in the Bronx. The veterans underwent skin biopsies and their skin cells were reprogrammed into induced pluripotent stem cells.
“Reprogramming cells into induced pluripotent stem cells is like taking cells virtually back in time to when they were embryonic and had the ability to generate all the cells in the body,” said Rachel Yehuda, Ph. .D., professor of psychiatry and neuroscience. , to Icahn Mount Sinai, director of mental health at the James J. Peters Veterans Affairs Medical Center and lead author of the paper.
“These cells can then be differentiated into neurons with the same properties as that person’s brain cells before trauma occurs to change how they function. The gene expression networks of these neurons reflect early gene activity resulting from very early genetic contributions and development, so they reflect the “pre-combat” or “pre-trauma” state of gene expression.
“Two people can experience the same trauma, but they won’t necessarily both develop PTSD,” explained Kristen Brennand, Ph.D., Elizabeth Mears and House Jameson Professor of Psychiatry at Yale School of Medicine and NYSCF—Robertson Stem Cell Investigator Alumna, who co-led the study.
“This kind of patterning in the brain cells of people with and without PTSD helps explain how genetics can make someone more susceptible to PTSD.”
To mimic the stress response that triggers PTSD, scientists exposed neurons derived from induced pluripotent stem cells to the stress hormone hydrocortisone, a synthetic version of the body’s cortisol that is used as part of the response.” fight or flight”.
“Adding stress hormones to these cells simulates the biological effects of combat, allowing us to determine how different gene networks are mobilized in response to stress exposure in brain cells,” explained Dr. Yehuda.
Using gene expression profiling and imaging, scientists found that neurons in people with PTSD were hypersensitive to this pharmacological trigger. The scientists were also able to identify specific gene networks that reacted differently after exposure to stress hormones.
Inside the cells of people with PTSD
Most similar PTSD studies to date have used blood samples from patients, but because PTSD is rooted in the brain, scientists need a way to capture how neurons in people with the disorder are affected. by stress. Therefore, the team chose to use stem cells because they are uniquely equipped to provide a patient-specific, non-invasive window into the brain.
“It’s difficult to get into the brain of a living person and extract cells from it. Stem cells are therefore our best way to examine the behavior of neurons in a patient,” said Dr. Brennand.
NYSCF scientists used their scalable, automated robotic system, the NYSCF Global Stem Cell Array, to create stem cells and then glutamatergic neurons from patients with PTSD. Glutamatergic neurons help the brain send excitatory signals and have previously been implicated in PTSD.
“Because this was the first study using stem cell models of PTSD, it was important to study large numbers of individuals,” said Daniel Paull, Ph.D., senior vice president of NYSCF, Discovery & Platform Development, who co-led the study. study.
“At the scale of this study, automation is key. With the Array, we can create standardized cells that allow meaningful comparisons across many individuals, highlighting key differences that could be essential for discovering new treatments.
Harnessing characteristics of stressed PTSD cells for new treatments
The team’s gene expression analysis revealed a set of genes that are particularly active in PTSD-prone neurons following their exposure to stress hormones.
“Importantly, the genetic signature we found in neurons was also apparent in brain samples from deceased people with PTSD, which tells us that stem cell models provide a fairly accurate reflection of what happens in the brains of living patients,” Dr. Paull noted.
Additionally, distinctions between how PTSD and non-PTSD cells responded to stress could be informative in predicting which people are at higher risk for PTSD.
“What’s really exciting about our findings are the opportunities they provide for accelerating the diagnosis and treatment of PTSD,” Dr. Paull continued.
“Importantly, having a robust stem cell model provides an ideal avenue for ‘in-dish’ drug screening, even among diverse patient populations.”
“We are working to find already approved drugs that could reverse the hypersensitivity that we observe in neurons,” Dr. Brennand added.
“That way, any drugs we discover will have the fastest possible path to helping patients.”
The researchers plan to continue to leverage their induced pluripotent stem cell models to further investigate the genetic risk factors highlighted by this study and to investigate how PTSD affects other brain cell types, helping to expand therapeutic discovery opportunities.
“NYSCF is incredibly proud to have generated the first-ever induced pluripotent stem cell models of individuals with PTSD in this landmark study in partnership with world-class scientists,” said Derrick Rossi, Ph.D. ., acting CEO of NYSCF.
“This collaborative work underscores the unique value of stem cell modeling for studying and demystifying challenging diseases, and for uncovering innovative strategies that could lead to urgently needed treatments.”
About this genetics and PTSD research news
Author: Press office
Source: Mount Sinai Hospital
Contact: Press Office – Mount Sinai Hospital
Image: Image is in public domain
Original research: Free access.
“Modeling of gene × environment interactions in PTSD using human neurons reveals diagnostic-specific glucocorticoid-induced gene expression” by Daniel Paull et al. Natural neuroscience
Modeling of gene × environment interactions in PTSD using human neurons reveals diagnostic-specific glucocorticoid-induced gene expression
Posttraumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown.
Here, we compared transcriptional responses to hydrocortisone exposure in glutamatergic neurons derived from human induced pluripotent stem cells (hiPSCs) and peripheral blood mononuclear cells (PBMCs) from veterans with PTSD. (not= 19 hiPSCs and not= 20 PBMC donors) and controls (not= 20 hiPSCs and not= 20 PBMC donors).
In neurons only, we observed diagnostic-specific glucocorticoid-induced changes in gene expression corresponding to PTSD-specific transcriptomic patterns found in human postmortem brains.
We observed glucocorticoid hypersensitivity in PTSD neurons and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence for a co-regulated network of transcription factors that mediates hyperresponsiveness to glucocorticoids in PTSD.
These results suggest that induced neurons represent a platform to examine the molecular mechanisms underlying PTSD, identify biomarkers of the stress response, and perform drug screening to identify novel therapies.