Stem cell study reveals how neurons from PTSD patients react to stress

Stem cell-derived neurons from combat veterans with post-traumatic stress disorder (PTSD) react differently to a stress hormone than those from veterans without PTSD, a finding that could provide insights into how genetics can make someone more susceptible to developing PTSD following trauma exposure.

The study, published October 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).

Post-traumatic stress disorder can develop following severe trauma and is an enormous 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 bridge this information gap, the research team studied a cohort of 39 combat veterans with and without PTSD who were 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 virtually taking cells back in time to when they were embryonic and had the ability to generate all the cells of the body,” said Rachel Yehuda, PhD, Professor of Psychiatry, and Neuroscience, at Icahn Mount Sinai, Director of Mental Health for the James J. Peters Veterans Affairs Medical Center, and senior author of the paper. “These cells can then be differentiated into neurons with the same properties as that person’s brain cells had before trauma occurred to change the way they function. The gene expression networks from these neurons reflect early gene activity resulting from genetic and very early developmental contributions, so they are a reflection of the ‘pre-combat’ or ‘pre-trauma’ gene expression state.”

“Two people can experience the same trauma, but they won't 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, who co-led 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 PTSD, 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.

“The addition of stress hormones to these cells simulates biological effects of combat, which allows us to determine how different gene networks mobilize in response to stress exposure in brain cells,” explained Dr. Yehuda.

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

Inside the Cells of PTSD-Affected Individuals
Most similar studies of PTSD to date have used blood samples from patients, but since PTSD is rooted in the brain, scientists need a way to capture how the neurons of individuals prone to the disorder are affected by stress. Therefore, the team opted to use stem cells, as they are uniquely equipped to provide a patient-specific, non-invasive window into the brain.

“You can’t easily reach into a living person’s brain and pull out cells, so stem cells are our best way to examine how neurons are behaving 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.

“As this was the first study using stem cell models of PTSD, it was important to study a large number of individuals,” said Daniel Paull, PhD, NYSCF Senior Vice President, Discovery & Platform Development, who co-led the study. “At the scale of this study, automation is essential. With the Array, we can make standardized cells that allow for meaningful comparisons between numerous individuals, pointing to key differences that could be critical for discovering new treatments.”

Leveraging the Hallmarks of Stressed PTSD Cells for New Treatments
The team’s gene expression analysis revealed a set of genes that were particularly active in PTSD-prone neurons following their exposure to stress hormones.

“Importantly, the gene signature we found in the neurons was also apparent in brain samples from deceased individuals with PTSD, which tells us that stem cell models are providing a pretty accurate reflection of what happens in the brains of living patients,” noted Dr. Paull.

Moreover, the distinctions between how PTSD and non-PTSD cells responded 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 for accelerating the diagnosis and treatment of PTSD," Dr. Paull continued. “Importantly, having a robust stem cell model provides an ideal avenue to drug screening ‘in the dish,’ even across diverse patient populations.”

“We’re working on finding already-approved drugs that could reverse the hypersensitivity we’re seeing in neurons,” added Dr. Brennand. “That way, any drugs we discover will have the fastest possible path to helping patients.”

The researchers plan to continue leveraging their induced pluripotent stem cell models to further investigate the genetic risk factors pinpointed by this study and to study how PTSD affects other types of brain cells, helping to broaden opportunities for therapeutic discovery.

A Study Enabled by Team Science
“What’s special about this study is that it could have only been done by this group,” said Dr. Brennand. “It involved some of the best clinicians in this space, incredible stem cell biologists, and amazing psychiatric geneticists. Each group has unique expertise, and none of this could have been accomplished by any one team alone.”

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

“NYSCF is incredibly proud to have generated the first-ever induced pluripotent stem cell models from individuals with PTSD as part of this landmark study in partnership with world-class scientists,” said NYSCF Interim CEO Derrick Rossi, PhD. “This collaborative work underscores the unique value of stem cell modeling for studying and demystifying challenging diseases, and for discovering innovative strategies that could lead to urgently 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 #: W81XWH-15-1-0706; Principal Investigator: Rachel Yehuda.)

About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population. 

Ranked 14th nationwide in National Institutes of Health (NIH) funding and among the 99th percentile in research dollars per investigator according to the  Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators and clinicians work within and across 34 academic departments and 35 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver diseases.

Icahn Mount Sinai offers highly competitive MD, PhD, and Master’s degree programs, with current enrollment of approximately 1,300 students. It has the largest graduate medical education program in the country, with more than 2,000 clinical residents and fellows training throughout the Health System. In addition, more than 550 postdoctoral research fellows are in training within the Health System.

A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, partners with faculty and trainees to pursue optimal commercialization of intellectual property to ensure that Mount Sinai discoveries and innovations translate into healthcare products and services that benefit the public.

Icahn Mount Sinai’s commitment to breakthrough science and clinical care is enhanced by academic affiliations that supplement and complement the School’s programs.

Through the Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk, and others.

The Icahn School of Medicine at Mount Sinai is located in New York City on the border between the Upper East Side and East Harlem and classroom teaching takes place on a campus facing Central Park. Icahn Mount Sinai’s location offers many opportunities to interact with and care for diverse communities. Learning extends well beyond the borders of our physical campus, to the eight hospitals of the Mount Sinai Health System, our academic affiliates, and globally.
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*Mount Sinai Health System Member Hospitals: The Mount Sinai Hospital; Mount Sinai Queens; Mount Sinai Beth Israel; Mount Sinai West; Mount Sinai Morningside Mount Sinai Brooklyn; New York Eye and Ear Infirmary of Mount Sinai; and Mount Sinai South Nassau.

About The James J. Peters Veterans Affairs Medical Center
The Bronx (James J. Peters) VAMC is a tertiary care medical center and Clinical Referral Level 1b facility that provides a broad range of inpatient and outpatient health care services. The facility is proudly affiliated with three of the premier academic medical institutions in New York City: The Icahn School of Medicine at Mount Sinai and Mount Sinai Health System, the Hospital for Special Surgery, and Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital. These affiliations enhance our research ability to provide the best in patient care and assure state-of-the-art medical expertise for the benefit of our Veteran patients.

About New York Stem Cell Foundation Research Institute
The New York Stem Cell Foundation (NYSCF) Research Institute is an independent non-profit organization accelerating cures and better treatments for patients through stem cell research. The NYSCF global community includes over 200 researchers at leading institutions worldwide, including the NYSCF – Druckenmiller Fellows, the NYSCF – Robertson Investigators, the NYSCF – Robertson Stem Cell Prize Recipients, and NYSCF Research Institute scientists and engineers. The NYSCF Research Institute is an acknowledged world leader in stem cell research and in the development of pioneering stem cell technologies, including the NYSCF Global Stem Cell Array®, which is used to create cell lines for laboratories around the globe. NYSCF focuses on translational research in an accelerator model designed to overcome barriers that slow discovery and replace silos with collaboration.

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