Stem Cell Study Reveals How Neurons From PTSD Patients React to Stress
First induced pluripotent stem cell model of PTSD offers insights into underlying genetics and opportunities for new therapies
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 (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.
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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.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.