Study uses pluripotent stem cell models to examine stress response in PTSD patients

Study uses pluripotent stem cell models to examine stress response in PTSD patients

Stem cell-derived neurons from combat veterans with post-traumatic stress disorder (PTSD) respond differently to a stress hormone than those from veterans without PTSD. This finding could shed light on how genetics can make someone more susceptible to developing PTSD after a traumatic exposure.

The study, published Oct. 20 in Nature 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).

Posttraumatic stress disorder can develop following severe trauma and represents a tremendous public health problem for both veterans and civilians. However, the extent to which genetic and environmental factors contribute to individual clinical outcomes remains unknown. To address this information gap, the research team examined a cohort of 39 combat veterans with and without PTSD recruited from the James J Peters Veterans Affairs Medical Center in the Bronx. Veterans underwent skin biopsies and their skin cells were reprogrammed into induced pluripotent stem cells.

Reprogramming cells into induced pluripotent stem cells is like essentially taking cells back to the time when they were embryonic and had the ability to generate all of the body's cells. These cells can then be differentiated into neurons with the same properties that person's brain cells had before the trauma to change how they function. The gene expression networks of these neurons reflect early gene activity resulting from genetic and very early developmental contributions, so they reflect the “pre-battle” or “pre-trauma” gene expression state.”

Rachel Yehuda, PhD, professor of psychiatry and neuroscience at Icahn Mount Sinai, director of mental health at James J. Peters Veterans Affairs Medical Center, and senior author

“Two people can experience the same trauma, but they do not necessarily both develop PTSD,” explained Kristen Brennand, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry at Yale School of Medicine and a NYSCF – Robertson Stem Cell Investigator Alumna co-leader of the study. “This type of modeling in brain cells from people with and without PTSD helps explain how genetics can make someone more susceptible to PTSD.”

To mimic the stress response that triggers post-traumatic stress disorder, the scientists exposed the induced pluripotent stem cell-derived neurons to the stress hormone hydrocortisone, a synthetic version of the body's own cortisol that is used as part of the "fight-or-flight" response.

“Adding stress hormones to these cells simulates the biological effects of a fight, allowing us to determine how different gene networks mobilize in brain cells in response to stress exposure,” explained Dr. Yehuda.

Using gene expression profiling and imaging, the scientists found that neurons from people with PTSD were hypersensitive to this pharmacological trigger. The scientists were also able to identify the specific gene networks that responded differently to exposure to the stress hormones.

In the cells of people affected by PTSD

To date, most comparable studies on PTSD have used blood samples from patients. But because PTSD is rooted in the brain, scientists need to capture how the neurons of people susceptible to the disorder are affected by stress. Therefore, the team decided to use stem cells because they are uniquely suited to providing a patient-specific, non-invasive window into the brain.

"You can't just reach into a living person's brain and pull out cells, so stem cells are our best option for studying how neurons behave in a patient," said Dr. Brennand.

NYSCF scientists used their scalable, automated robotic system; The NYSCF Global Stem Cell Array® is designed to generate stem cells and then glutamatergic neurons from patients with PTSD. Glutamatergic neurons help the brain send excitatory signals and have previously been linked to PTSD.

“Because this was the first study using stem cell models of PTSD, it was important to study a large number of people,” said Daniel Paull, PhD, NYSCF Senior Vice President, Discovery & Platform Development, who co-led the study. "At the level of this study, automation is essential. The array will allow us to create standardized cells that allow meaningful comparisons across numerous individuals and highlight key differences that could be critical to discovering new treatments."

Harnessing the characteristics of stressed PTSD cells for new treatments

The team's gene expression analysis revealed a number of genes that were particularly active in PTSD-prone neurons after exposure to stress hormones.

“Importantly, the gene signature we found in the neurons was also visible in brain samples from deceased individuals with PTSD, showing us that stem cell models provide a fairly accurate picture of what is happening in the brains of living patients,” noted Dr. Paull.

Additionally, the differences between the response of PTSD and non-PTSD cells to stress could be informative in predicting which individuals are at higher risk for PTSD.

“What’s really exciting about our findings is the opportunities they offer to accelerate the diagnosis and treatment of PTSD,” continued Dr. Paull continued. “Importantly, a robust stem cell model provides an ideal opportunity for “in-dish” drug screening, even across diverse patient populations.”

“We are working to find already approved drugs that could reverse the hypersensitivity we see in neurons,” added Dr. Brennand added. “This way, any drugs we discover will find the fastest possible way to help patients.”

The researchers plan to continue using their induced pluripotent stem cell models to further investigate the genetic risk factors identified in this study and to examine how PTSD affects other types of brain cells, thereby expanding the possibilities for therapeutic discoveries.

A study enabled by team science

“The special thing about this study is that it could only be carried out by this group,” said Dr. Brennand. "This involved some of the best clinicians in the field, incredible stem cell biologists and great psychiatric geneticists. Each group has unique expertise, and none of this could have been achieved by one team alone."

“This study is a real testament to the power of team science,” added Dr. Paull added. “When researchers join forces, we can ask bigger questions, make bigger discoveries and hopefully make a bigger difference for patients.”

“NYSCF is incredibly proud to have created the first induced pluripotent stem cell models of individuals with PTSD through this groundbreaking study in collaboration with world-class scientists,” said NYSCF Interim CEO Derrick Rossi, PhD. “This collaborative work highlights the unique value of stem cell modeling for studying and demystifying challenging diseases, as well as discovering innovative strategies that could lead to much-needed treatments.”

This work was supported by a grant to the Icahn School of Medicine at Mount Sinai from the Office of the Assistant Secretary of Defense for Health Affairs through the U.S. Army Medical Research and Material Command for Extramural Medical Research Department of Defense (Award Number: W81XWH-15-1-0706; Principal Investigator: Rachel Yehuda.)

Source:

Mount Sinai Health System

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