USF Health-UAB study indicates that lipid mediators may offer new targets for more personalized heart failure diagnosis and treatment

The new study profiled bioactive lipids in blood samples collected from hospitalized black and white patients soon after a severe heart attack.

TAMPA, Fla (May 4, 2020) — Black men and women have higher incidences than whites of developing advanced heart failure following a heart attack. Despite racial disparities in heart attacks (a leading contributor to heart failure), and rehospitalizations and deaths caused by heart disease, the underlying physiology accounting for worse cardiovascular outcomes among blacks is poorly understood.

A new study published May 4 in ESC Heart Failure profiles bioactive lipids in blood samples from hospitalized black and white patients soon after a severe heart attack. The preliminary research was conducted by a team at the University of South Florida Health (USF Health) Morsani College of Medicine and the University of Alabama at Birmingham. The researchers wanted to delineate potential differences in the immune-responsive processes needed to safely clear (resolve) acute inflammation after heart attack-induced tissue injury, with the aim of finding more individualized therapies for heart failure.

“Metabolic and leukocyte-responsive signaling control the acute inflammation needed for timely cardiac repair after a heart attack. But inflammation that is not cleared and remains long-term plays a key role in the pathology leading to heart failure,” said lead author Ganesh Halade, PhD, associate professor of cardiovascular sciences at the Morsani College of Medicine and a member of the USF Health Heart Institute.

“Understanding race and sex-based differences in inflammation and its resolution will help us develop more personalized diagnoses and treatments to delay or prevent heart failure.”

A mouse model study published by Dr. Halade last month discovered that heart repair occurs faster in female mice than males after a heart attack, which improves survival and delays cardiac failure.

In this human study, the researchers collected blood plasma from 53 patients, grouped by race and sex, within 24 to 48 hours after a heart attack. Baseline acute injury caused by the heart attack was similar in all the patients, and so were their ages and body mass indexes. No significant sex-or race-specific differences were detected in total cholesterol, HDL, LDL or triglyceride levels – all indicators (biomarkers) currently used by clinicians to help predict risk and manage cardiovascular disease. Measures of various subtypes of leukocytes (cells that regulate immune fitness) were similar across all patients.

Lead author Ganesh Halade, PhD, associate professor of cardiovascular sciences, USF Health Morsani College of Medicine

Looking for distinct bioactive lipid “signatures,” or inflammatory biomarkers, that might predict poorer cardiovascular outcomes after heart attack, the researchers measured three major polyunsaturated fatty acids: arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). These omega fatty acids circulate in blood and depend upon what people eat. Also analyzed were dozens of specific proresolving mediator (SPM) indicators and a few other signaling molecules that form when these fatty acids metabolize in response to immune activation.

Overall, black patients showed higher concentrations of the three activated fatty acids after a heart attack than white patients, the researchers found. The comparative analyses of SPMs showed that resolvin E1, a potent proresolving mediator of inflammation derived from the fatty acid EPA, was significantly lower in black men and women than in whites. An earlier major clinical trial linked EPA with reduced ischemic events such as heart attack and stroke in patients with high risk for, or existing, cardiac disease, and another showed that high levels of EPA significantly decreased the risk of heart failure.

The researchers conclude that bioactive lipids are key for diagnosis and treatment of cardiac repair after heart attack to delay heart failure.

Randomized controlled clinical trials will be needed to definitively determine whether distinct SPM signatures can be used to predict, diagnose, treat or prevent heart failure following a heart attack, Dr. Halade said. “If we can stratify risk among larger patient groups to determine who is deficient in SPMs critical for cardiac repair, we may be able to restore those targeted SPMs to improve outcomes.”

The study was supported by grants from the National Institutes of Health.

Heart failure affects about 6.5 million adults nationwide and leads to one in 8 deaths each year, according to the Centers for Disease Control and Prevention. The condition usually develops as the heart gradually loses its ability to pump enough blood through the body.

New USF Health research on endothelial-derived microvesicles, using models of sepsis, may be useful for better diagnosis and treatment of inflammatory or infectious diseases

A new preclinical study by the University of South Florida Health (USF Health) Morsani College of Medicine sheds light on how tiny bubble-like particles flowing in the blood can serve as diagnostic markers for certain diseases while also contributing to disease progression.

Microvesicles (green) interacting with target endothelial cells (nuclei stained blue) to increase both stress fiber formation (red) and activation of cellular contraction proteins (yellow). The interaction contributes to greater vascular wall barrier permeability (leakage). Image courtesy of Victor Chatterjee (University of South Florida), originally published by Oxford University Press, Cardiovascular Research, https://doi.org/10.1093/cvr/cvz238

Cells lining the inner surface of blood vessels, called endothelial cells, have the ability to package and release microscopic vesicles (0.1 to 1 micrometer in diameter) into the blood circulation. These microvesicles carry unique cargo of molecules under different health or disease conditions; thus, by identifying their specific cargo content or molecular signature, doctors can better diagnose the nature and extent of a medical problem.

Researchers in the laboratory of Sarah Yuan, MD, PhD, at the USF Health Department of Molecular Pharmacology and Physiology, discovered that endothelial cells produce microvesicles containing a high level of c-Src protein during sepsis, a life-threatening condition that causes systemic inflammation and multiple organ failure. Their study, conducted using cell cultures and an animal model of sepsis, was recently reported in Cardiovascular Research, a highly rated journal sponsored by the European Society of Cardiology.

Most intriguingly, the researchers found that in addition to providing a unique marker that signifies the status of inflammation in blood vessels, these c-Src enriched microvesicles play an active role in causing vascular wall injury and barrier leakage.

Victor Chatterjee, MD, PhD, a postdoctoral fellow in the Department of Molecular Pharmacology and Physiology, was the paper’s first author. He works in the laboratory of departmental chair Sarah Yuan, MD, PhD. | Photo by Allison Long, USF Health Communications and Marketing

“Microvesicles produced by inflamed endothelial cells circulate in the blood and target healthy barrier cells by unloading their bioactive cargo into receiving cells. They ‘tell’ the receiving cells to change behavior, leading to an increased permeability of the barrier,” said first author Victor Chatterjee, MD, PhD, a postdoctoral fellow working in Dr. Yuan’s lab.

Like the breech of a protective levy, increased permeability of the endothelial barrier allows blood fluids and proteins to leak through the blood vessel wall into surrounding tissues. Because this leak process underlies sepsis, traumatic injury, atherosclerosis, cancer, and several types of inflammatory or immunological disorders, the authors suggest that endothelial-derived microvesicles may have potential applications in developing new molecular markers or therapeutic targets for better diagnosis and treatment of these diseases.

This paper also reports an in-depth analysis of the molecular mechanisms underlying vascular leakage caused by endothelial derived microvesicles.

A key finding is that the circulating microparticles are highly interactive. They bind to the membrane of targeted endothelial cells and get inside these cells, where they unload c-Src cargo to turn on the signal for cell contraction and cell-to-cell junction opening. Since junctions are critical structures that “glue” neighboring cells together to form the vascular wall barrier, opening them results in blood leakage.

Dr. Yuan, a member of the USF Health Heart Institute, was senior author of the NIH-supported study published in Cardiovascular Research.

In an effort to translate their benchwork to bedside care, the USF Health researchers plan to use blood samples from human patients to determine if and how the molecular signature of microvesicles change over time or correlate with disease severity, Dr. Chatterjee said.  A better understanding of how these tiny cargo carriers function in the human disease process could help guide physicians in better managing infectious or inflammatory diseases, he said.

The senior author of the Cardiovascular Research paper is Dr. Yuan, professor and department chair, who holds the USF Health Deriso Endowed Chair in Cardiovascular Disease. Dr. Yuan’s research has been supported by the National Institutes of Health: National Heart, Lung, and Blood Institute, and National Institute of General Medical Sciences.

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The founding director of the USF Health Heart Institute has a passion for innovation, translational medicine and entrepreneurship.

Samuel A. Wickline, MD, has parlayed his expertise in harnessing nanotechnology for molecular imaging and targeted treatments into an impressive $1-million portfolio of National Institutes of Health awards, multiple patents and four start-up biotechnology companies.

“We’ve developed nanostructures that can carry drugs or exist as therapeutic agents themselves against various types of inflammatory diseases, including, cancer, cardiovascular disease, arthritis and even infectious diseases like HIV,” said Dr. Wickline, who arrived at USF Health last month from the Washington University School of Medicine in St. Louis.

Dr. Wickline: “Innovation is not just about having a new idea, it’s about having a useful idea.”

 Dr. Wickline comments on how being a physician adds perspective to the science he conducts.

At Washington University, Dr. Wickline, a cardiologist, most recently was J. Russell Hornsby Professor in Biomedical Sciences and a professor of medicine with additional appointments in biomedical engineering, physics, and cell biology and physiology.

“I like the challenge of building things,” he said.

In St. Louis, he built a 29-year career as an accomplished physician-scientist keenly interested in translating basic science discoveries into practical applications to benefit patients. He served as chief of cardiology at Jewish Hospital, developed one of the first cardiac MRI training and research programs in the country, helped establish Washington University’s first graduate program in biomedical engineering, and led a university consortium that works with academic and industry partners to develop medical applications for nanotechnology.

At USF, there will be no shortage of challenging opportunities to build.

Building the USF Health Heart Institute

A major part of Dr. Wickline’s new job is helping to design, build and equip the Heart Institute. Most importantly, he will staff the state-of-the-art facility with a critical interdisciplinary mix of top biomedical scientists (including immunologists, molecular biologists, cell physiologists and genomics experts), who investigate the root causes of heart and vascular disease with the aim of finding new ways to detect, treat and prevent them. The Heart Institute will be co-located with new Morsani College of Medicine in downtown Tampa; construction on the combined facility is expected to begin later this year.

“I have been impressed by the energy and commitment here at the University of South Florida to invest substantial resources in a heart institute,” Dr. Wickline said. “I believe we have a lot to offer in terms of bench-to-bedside research that could solve some of the major cardiovascular problems” like atherosclerosis or heart failure.

“We want to put together a program that supplies the appropriate core facilities to attract the best and brightest researchers to this cardiovascular institute.”

Cardiovascular disease is the leading cause of death in the United States and worldwide, so exploring potential new treatment options is critical. One of the Heart Institute’s driving themes will be advancing concepts and findings that prove promising in the laboratory into projects commercialized for clinical use, Dr. Wickline said.

“Our goal is to make a difference in the lives of patients,” he said. “Innovation is not just about having a new idea, it’s about having a useful idea.”

Dr. Wickline also serves as associate dean for cardiovascular research and a professor of cardiovascular sciences at the Morsani College of Medicine. He holds the Tampa General Endowed Chair for Cardiovascular Research created last year with a gift from USF’s primary teaching hospital.

With Washington University colleague Hua Pan, PhD, a biomedical engineer and expert in molecular biology, Dr. Wickline is re-building his group at USF. Dr. Pan was recently recruited to USF as an assistant professor of medicine to continue her collaborations with Dr. Wickline.

 An example of Dr. Wickline’s group using nanotechnology to help combat atherosclerosis.

Dr. Wickline’s lab focuses on building nanoparticles to deliver drugs or other therapeutic agents to specific cell types, or targets.

Designing nanoparticles to “kill the messenger”

Dr. Wickline’s lab focuses on building nanoparticles – shaped like spheres or plates, but 10 to 50 times smaller than a red blood cell – to deliver drugs or other therapeutic agents through the bloodstream to specific cell types, or targets. These tiny carrier systems can effectively deliver a sizeable dosage directly to a targeted tissue, yet only require small amounts of the treatment in the circulation to reduce the risk of harmful side effects.

Some types of nanoparticles can carry image-enhancing agents that allow researchers to quantify where the illuminated particles travel, serving as beacons to specific molecules of interest, and enabling one to determine whether a therapeutic agent has penetrated its targeted site, Dr. Wickline said.

Dr. Wickline also is known for designing nanoparticles derived from a component of bee venom called melittin. While bee venom itself is toxic, Dr. Wickline’s laboratory has detoxified the molecule and modified its structure to produce a formula that allows the nanoparticles to carry small interfering (siRNA), also known as “silencing RNA,” or other types of synthetic DNA or RNA strand.

Among other functions, siRNA can be used to inhibit the genes that lead to the production of toxic proteins. Many in the nanotechnology research and development community are working to make siRNA treatment feasible as what Dr. Wickline calls “a message killer,” but the challenges have been daunting.

“The big challenge in the field of siRNA, and many companies have failed at this, is how to get the nanostructure to the cells so that the siRNA can do what it’s supposed – hit its target and kill the messenger — without being destroyed along the way, or having harmful side effects,” Dr. Wickline said. “We figured out how to engineer into a simple peptide all of the complex functionality that allows that to happen.”

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 Dr. Wickline comments on the underlying similarities between cardiovascular disease and cancer.

Different targets, same delivery vehicle

In a recent series of experiments in mice, Dr. Wickline and colleagues have shown that silencing RNA messages delivered by nanoparticle to a specific type of immune cell known as a macrophage – a “big eater” of fat – actually shrinks plaques that accumulate inside the walls of the arteries during atherosclerosis, one of the main causes of cardiovascular disease. The build-up of atherosclerotic plaques with fat-laden macrophages narrows, weakens and hardens arteries, eventually reducing the amount of oxygen-rich blood delivered to vital organs.

This type of plaque-inhibiting nanotherapy could be useful in aggressive forms of atherosclerosis where patients have intractable chest pain or after an acute heart attack or stroke to prevent a secondary cardiac event, Dr. Wickline said.

In another study, Washington University School of Medicine researchers investigated the potential of the siRNA nanoparticle designed by co-investigators Dr. Pan and Dr. Wickline in treating the inflammation that may lead to osteoarthritis, a degenerative joint disease that is a major cause of disability in the aging population. The nanoparticles — injected directly into injured joints in mice to suppress the activity of the molecule NF-κB — reduced local inflammation immediately following injury and reduced the destruction of cartilage. The findings were reported September 2016 in the Proceedings of the National Academy of Sciences.

Previously, Dr. Wickline said, the Washington University group had shown that nanoparticles delivered through the bloodstream inhibited inflammation in a mouse model of rheumatoid arthritis. And, another laboratory at the University of Kentucky is studying whether locally injected siRNA nanoparticles can quell the bacterial inflammation that can lead to a serious gum disease known as periodontitis. Other collaborating labs are using these nanoparticles in pancreatic, colon, and ovarian cancers with good effects.

“The specific targets in these cases may be different, but the nice thing about this kind of delivery system for RNA interference is that the delivery agent itself, the nanostructures, are the same,” Dr. Wickline said. “All we have to do is change out a little bit of the genetic material that targets the messages and we’re set up to go after another disease. So it’s completely modular and nontoxic.”

The St. Louis-based biotechnology company Trasir Therapeutics is developing these peptide-based nanocarriers for silencing RNA to treat diseases with multiple mechanisms of inflammation. Dr. Wickline co-founded the company in 2014 and continues to serve as its chief scientific officer.

Dr. Wickline with colleague Hua Pan, PhD, a biomedical engineer with expertise in molecular biology.

 Inhibiting chronic inflammation without getting rid of beneficial immune responses.

Calming the destructive cycle of inflammation

Dr. Wickline’s work is supported by several NIH RO1 grants, including one from the National Heart, Lung and Blood Institute to develop and test nanotherapies seeking to interrupt inflammatory signaling molecules and reduce the likelihood of thrombosis in acute cardiovascular syndromes.

In essence, Dr. Wickline said, he is interested in suppressing chronic inflammation, without disrupting the beneficial functions of surveillance by which the immune system recognizes and destroys invading pathogens or potential cancer cells.

“If you can inhibit the ongoing inflammation associated with (inappropriate) immune system response, you inhibit the positive feedback cycle of more inflammation, more plaques, more damage and more danger,” he said. “If you can cool off inflammation by using a message killer that says (to macrophages) ‘don’t come here, don’t eat fat, don’t make a blood clot’ – that’s what we think could be a game changer.”

Another NIH grant has funded collaborative work to develop an image-based nanoparticle that detects where in a compromised blood vessel too much blood clotting (hypercoagulation) occurs, and delivers potent anti-clotting agent only to that site. Formation of abnormal blood clots can trigger a heart attack when a clot blocks an artery that leads to heart muscle, or a stroke when a clot obstructs an artery supplying blood to the brain.

Because this site-specific nanotherapy targets only areas of active clotting, it may provide a safer, more effective approach against cardiac conditions like atrial fibrillation and acute heart attack than existing anticoagulant drugs such as warfarin and newer blood thinners like Xarelto® (rivaroxoban) or Eliquis® (apixiban), all which work systemically and come with raised risk for serious bleeding, Dr. Wickline said.

In a study published last year in the journal Arteriosclerosis, Thrombosis, and Vascular Biology, Dr. Wickline and colleagues found that nanoparticles delivering a potent inhibitor of thrombin, a coagulant protein in blood that plays a role in inflammation, not only reduced clotting risk but also rapidly healed blood vessel endothelial barriers damaged during plaque growth.

The preclinical work showed the experimental treatment “is actually an anti-atherosclerotic drug as well as an anti-clotting drug, so there are many potential applications,” Dr. Wickline said.

Dr. Wickline received his MD degree from the University of Hawaii School of Medicine. He completed a residency in internal medicine, followed by clinical and research fellowships in cardiology at Barnes Hospital and Washington University, where he joined the medical school faculty in 1987.

He has authored more than 300 peer-reviewed papers and holds numerous U.S. patents. Dr. Wickline is a fellow of the American College of Cardiology and the American Heart Association, and a 2014 recipient of the Washington University Chancellor’s Award for Innovation and Entrepreneurship.

– Photos by Sandra C. Roa and Eric Younghans

Jerome Breslin studies what happens when the endothelial barrier is breeched by traumatic injury and inflammation

Traumatic injury is the leading cause of death among people ages 1 to 44 in the United States. The body’s inflammatory response accompanying massive injury can severely complicate the resuscitation of trauma victims, worsen clinical outcomes and often lead to multiple organ failure.

In his laboratory at the USF Health Morsani College of Medicine, Jerome Breslin, PhD, and colleagues study microvascular hyperpermeability, that is, the “excessively leaky” small blood vessels that are a hallmark of systemic inflammation.  Their aim is to find new, more effective ways to treat trauma and prevent early death, but their work also has implications for the treatment of lymphedema, wound healing and arteriosclerosis.

Jerome Breslin, PhD, can do live imaging of vascular endothelial cells under a microscope that he helped build.

In particular, Dr. Breslin, an associate professor in the Department of Molecular Pharmacology and Physiology, looks at what happens when the protective barrier of endothelial cells forming an interface between circulating blood and tissues outside the blood vessel network is compromised by traumatic injury and inflammation.

Leaky blood vessels: The soaker hose analogy

“These capillaries are like soaker hoses used to water plants, that leak out fluid carrying proteins and other nutrients in addition to delivering oxygen to surrounding tissue,” Dr. Breslin said. “In patients who have undergone trauma or major surgery, blood pressure drops in part because the wall of the hose becomes too leaky. There is less fluid in the blood vessels and more flowing out into nearby tissues, which can cause damage and impair the function of some organs.”

In addition to investigating ways to prevent excessive blood vessel leakage, Dr. Breslin’s lab focuses on how to return the leaked fluid back into the blood by the lymphatic vessels.  As a result, his team spends a lot of time studying the pumping function of the lymphatic system, which manages fluid levels in the body. Swelling, or edema, occurs when it fails to drain off excess fluid.

Dr. Breslin’s work is currently supported by two National Institutes of Health RO1 grants totaling more than $2 million.

Dr. Breslin with two undergraduate students who conduct research in his laboratory: Andrea Burgess (American Physiological Society IOSP Summer Fellow) and Sara Spampinato, center (NIH Diversity Grant recipient).

 Dr. Breslin comments on his approach to research problems.

The most recent award from the NIH’s National Institute of General Medical Sciences focuses on testing whether a class of drugs that activate the S1P1 receptor may keep blood vessels from leaking too much and stabilize blood pressure following trauma.

In this project, Dr. Breslin will use the first rat model combining alcohol intoxication and hemorrhagic shock to induce excessive leakiness in small blood vessels. He will evaluate whether fluid containing sphingosine-1-phosphate (S1P) reduces the blood vessel permeability, thereby restoring normal blood pressure and fluid balance. If so, Dr. Breslin said, drugs similar to S1P, a bioactive lipid that prevents cell death, may offer a more effective way for paramedics and physicians to resuscitate trauma patients than the standard IV fluid therapy now administered.  That standard fluid resuscitation protocol works particularly poorly in alcohol-intoxicated victims suffering major blood loss, a significant portion of all trauma cases coming through emergency rooms, he said.

With the second award, a competitive renewal from the NIH’s National Heart, Blood and Lung Institute, Dr. Breslin and colleagues are studying the molecular and cellular mechanisms that may regulate and resolve microvascular leakage following inflammation caused by traumatic injury.

Dr. Breslin points to a human heart valve suspended in a test tube solution. His group plans to study the microvessels within heart valves.

Unexpected finding leads to “new way of thinking”

Previous work by his group using live imaging of vascular endothelial cells under a microscope demonstrated that when the edges of these cells make contact with their neighboring cells they appear very active and are constantly remodeling, or changing shape — rapidly opening up holes at cell junctions and then closing back up. This finding, published in the journal PLOS One, countered one of the conventional theories that endothelial cells were more rigid at the junctions where they connect and adopted a contracted state during inflammation.

“It was an unexpected finding that changed our thinking about how these cells behaved,” Dr. Breslin said.

This led the researchers to begin to question the prevailing view about the role actin stress fibers — threadlike structures involved in cell stability, adhesion and movement — play in disrupting the endothelial barrier function.

Further preclinical studies by Dr. Breslin and others over several years showed that in response to an inflammatory agent actin stress fibers cause endothelial cells to spread out, not contract, at the junctions. The USF researchers published evidence in the American Journal of Physiology: Cell Physiology that actin stress fiber formation may be a reaction to, rather than a cause of, reduced integrity of the endothelial barrier that protects against excessive fluid leakage.

Earlier this year, Dr. Breslin was first author on a study appearing in the Journal of the American Heart Association showing that the signaling protein Rnd3 reduced leakage of small blood vessels when delivered a new way in a rat model of hemorrhagic shock. The researchers suggested Rnd3 (or analog drugs) might offer an anti-inflammatory treatment to repair the endothelial barrier compromised by prolonged and uncontrolled inflammation.

  Dr. Breslin talks about his most exciting experiment

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Live imaging of endothelial microvascular cells at 600x magnification shows the dynamic movement of the protruding cell edges (local lamellipodia). Videoclip courtesy of Jerome Breslin, PhD. 

Heart Institute, former mentor a draw to USF

Dr. Breslin joined USF in 2012 from Louisiana State University Health Sciences Center in New Orleans, where he was an assistant professor of physiology.  He received his PhD in pharmacology and physiology from Rutgers University – New Jersey Medical School in Newark, NJ.  His postdoctoral training was conducted at both Texas A&M and the School of Medicine at the University of California Davis, where he was mentored by Sarah Yuan, MD, PhD, the chair of Molecular Pharmacology at Physiology at Morsani College of Medicine who is nationally recognized for her translational research on the regulation of microcirculation.

The opportunity to be part of a growing university, join core faculty who will help build a Heart Institute advancing bench-to-bedside cardiovascular research, and work again with Dr. Yuan attracted him to USF Health, Dr. Breslin said.

“Dr. Yuan was a great mentor to me when I was a postdoctoral fellow,” he said. “This has reopened our scientific collaborations and now we’re mentoring a student together.”

Dr. Breslin, center, with some members of his laboratory.

  His advice to emerging scientists

Dr. Breslin is a fellow of the American Physiological Society Cardiovascular Section and a member of The Microcirculatory Society and the American Heart Association.  He is associate editor of the journal Microcirculation and a member of the editorial board of PLOS One.  He has authored or co-authored nearly 40 articles in peer-reviewed journals.

Dr. Breslin serves on two NIH special emphasis panels, one on lymphatics and another for the Intramural Postdoctoral Research Associate Program.  He is also a grant reviewer for the Association of American Medical Colleges (AAMC) Innovations in Research and Research Education Awards.

Something you may not know about Dr. Breslin

To help pay for tuition while earning his master’s degree in biology, Dr. Breslin worked as a park ranger in Somerset County, N.J, for a couple of summers.

No stranger to outdoor activities, including camping, as a teen Dr. Breslin attained the rank of Eagle Scout, the highest achievement in the Boy Scouting program.  His connection with scouting continues today as committee chair for his 13-year-old son’s Boy Scout troop.

Dr. Breslin’s Scouting experiences included learning wilderness survival skills, such as how to build a shelter from scratch in the woods or navigating a group of boys through the wilderness without a map and compass, or a smartphone for that matter. They were instrumental, he said, in helping him develop the resourcefulness and leadership skills he hopes to impart to the emerging scientists he mentors in his laboratory

In case you’re wondering, one of the most challenging of the merit badges he earned as a Boy Scout: bugling.

Photos and audioclips by Sandra C. Roa, USF Health Communications and Marketing

A USF preclinical study shows transplanted human bone marrow stem cells preferentially migrate to the spleen, reducing systemic inflammation of later-stage stroke

Tampa, FL (Sept. 15, 2015) — Stroke injures the brain, but a new University of South Florida study indicates an abdominal organ that plays a vital role in immune function, the spleen, may be a target for treating stroke-induced chronic inflammation leading to further brain cell death.

Neuroscientists at the USF Center of Excellence for Aging and Brain Repair found that human bone marrow stem cells intravenously administered to post-stroke rats preferentially migrated to the spleen and reduced the inflammatory-plagued secondary cell death associated with stroke progression in the brain. The study is reported in the September 2015 issue of the American Heart Association journal Stroke.

Cesario Borlongan, PhD, the study’s principal investigator, is a pioneer in stem cell therapy research for stroke. He directs the USF Center of Excellence for Aging and Brain Repair.

The USF study helps resolve a perplexing observation by many scientists evaluating the effects of stem cell therapies: Functional recovery occurs in experimental models of neurological disorders, including stroke, despite little or mediocre survival of transplanted stem cells within the injured brain.

“Our findings suggest that even if stem cells do not enter the brain or survive there, as long as the transplanted cells survive in the spleen the anti-inflammatory effects they promote may be sufficient enough to therapeutically benefit the stroke brain,” said principal investigator Cesario Borlongan, PhD, professor and director of the USF Center of Excellence for Aging and Brain Repair.

Stroke is a leading cause of death and the number one cause of chronic disability in the United States, yet treatment options are limited.  Stem cell therapy has emerged as a potential treatment for ischemic stroke, but most preclinical studies have looked at the effects of stem cells transplanted during acute stroke – one hour to 3 days after stroke onset.

Following acute stroke, an initial brain attack caused by lack of blood flow, the blood-brain barrier is breeched, allowing the infiltration of inflammatory molecules that trigger secondary brain cell death in the weeks and months that follow. This acerbated inflammation is the hallmark of chronic stroke.

The USF researchers intravenously administered human bone marrow stem cells to rats 60 days following stroke onset – the chronic stage. The transplanted stem cells were attracted predominantly to the spleen; the researchers found 30-fold more stem cells survived in this peripheral organ than in the brain.  Once in the spleen, the stem cells dampened an inflammatory signal (tumor necrosis factor) activated immediately after stroke and prevented the migration from spleen to the compromised brain of harmful macrophages that stimulate inflammation.

This reduced systemic inflammation correlated with significant decreases in the size of lesions caused by acute stroke in the striatum—a portion of the brain controlling movement. There was a trend toward prevention of additional neuron loss in the portion of the brain affecting memory and thinking.

“In the chronic stage of stroke, macrophages are like fuel to the fire of inflammation,” Dr. Borlongan said. “So if we can find a way to effectively block the fuel with stem cells, then we may prevent the spread of damage in the brain and ameliorate the disabling symptoms many stroke patients live with.”

The USF researchers next plan to test whether transplanting human bone marrow stem cells directly into the spleen will lead to behavioral recovery in post-stroke rats.

Dr. Borlongan with postdoctoral fellow Sandra Acosta, PhD, the study’s lead author.

The one drug approved for emergency treatment of stroke, the clot-busting drug tPA, must be administered less than 4.5 hours after onset of ischemic stroke, and  benefits only 3 to 4 percent of patients, Dr. Borlongan said. While more study is needed, evidence from USF and other groups thus far indicates stem cells may help provide a more effective treatment for stroke over a wider timeframe.

“Stem cells are not a magic bullet, but a combination of stem cells and other anti-inflammatory agents may lead to the optimal therapeutic benefit for stroke patients,” he said.

Lead study author Sandra Acosta, PhD, a postdoctoral fellow in the USF Department of Neurosurgery and Brain Repair, said targeting the spleen with stem cells or the anti-inflammatory molecules they secrete offers hope for treating chronic neurodegenerative diseases like stroke at later stages.

“We’ve shown (in an animal model) that it’s possible to stop disease progression 60 days after the initial stroke injury, when chronic inflammation in the brain was widespread,” she said. “If that can be replicated in humans, it will be powerful.”

The USF study was supported by grants from the National Institute of Neurological Disorders and Stroke and the James and Esther King Biomedical Research Foundation.

Article citation:
Sandra A. Acosta; Naoki Tajira; Jaclyn Hoover; Yuji Kaneko; and Cesar Borlongan, “Intravenous Bone Marrow Stem Cell Grafts Preferentially Migrate to Spleen and Abrogate Chronic Inflammation in Stroke,” Stroke, September 2015; DOI: 10.1161/STROKEAHA.115.009854.

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Photos by Sandra Roa, USF Health Communications and Marketing

Tampa, FL (June 28, 2013) — A cardiac hormone signaling receptor abundantly expressed both in inflamed tissues and cancers appears to recruit stem cells that form the blood vessels needed to feed tumor growth, reports a new study by scientists at the University of South Florida Nanomedicine Research Center. 

The research may lead to the development of new drugs or delivery systems to treat cancer by blocking this receptor, known as natriuretic peptide receptor A (NPRA).

The findings appeared online recently in the journal Stem Cells.

“Our results show that NRPA signaling by cancer cells produces some molecular factors that attract stem cells, which in turn form blood vessels that provide oxygen and nutrients to the tumor,” said the study’s principal investigator Subhra Mohapatra, PhD, associate professor in the Department of Molecular Medicine. “We showed that if the NPRA signal is blocked, so is the angiogenesis and, if the tumor’s blood supply is cut off it will die.” 

Subhra Mohapatra, PhD

Using both cultured cells and a mouse model, Dr. Mohapatra and her team modeled interactions to study the association between gene mutations and exposure to an inflammatory tissue microenvironment.

The researchers demonstrated that cardiac hormone NRPA played a key role in the link between inflammation and the development of cancer-causing tumors. Mice lacking NPRA signaling failed to induce tumors. However, co-implanting tumor cells with mesenchymal stem cells, which can turn into cells lining the inner walls of blood vessels, promoted the sprouting of blood vessels (angiogenesis) needed to promote tumor growth in NPRA- deficient mice, the researchers found. Furthermore, they showed that NRPA signaling appears to regulate key inflammatory cytokines involved in attracting these stem cells to tumor cells.

Dr. Mohapatra’s laboratory is testing an innovative drug delivery system using special nanoparticles to specifically target cancers cells like a guided missile, while sparing healthy cells. The treatment is intended to deliver a package of molecules that interferes with the cardiac hormone receptor’s ability to signal.

Dr. Mohapatra collaborated with Shyam Mohapatra, PhD, and Srinivas Nagaraj, PhD, both faculty members in the Nanomedicine Research Center and Department of Internal Medicine, on genetic and immunological aspects of the study.

The study was supported by the National Institutes of Health and a Florida Biomedical Research Grant.

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Research with rat models finds chronic inflammation, suppression of cell regeneration, and neuronal cell loss contribute to wide range of motor and cognitive deficits

TAMPA, FL  (Jan. 4, 2013) – Researchers from the University of South Florida and colleagues at the James A. Haley Veterans’ Hospital studying the long-term consequences of traumatic brain injury (TBI) using rat models, have found that, over time, TBI results in progressive brain deterioration characterized by elevated inflammation and suppressed cell regeneration. However, therapeutic intervention, even in the chronic stage of TBI, may still help prevent cell death.

Their study is published online in the current issue of the journal PLOS ONE.

“In the U.S., an estimated 1.7 million people suffer from traumatic brain injury,” said the study’s senior author Cesar V. Borlongan, PhD, professor and vice chair of the Department of Neurosurgery and Brain Repair at USF.  “In addition, TBI is responsible for 52,000 early deaths, accounts for 30 percent of all injury-related deaths, and costs approximately $52 billion yearly to treat.” 

While TBI is generally considered an acute injury, secondary cell death caused by neuroinflammation and an impaired repair mechanism accompany the injury over time, the authors said. Long-term neurological deficits from TBI related to inflammation may cause more severe secondary injuries and predispose long-term survivors to age-related neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and post-traumatic dementia.

Since the U.S. military has been involved in conflicts in Iraq and Afghanistan, the incidence of traumatic brain injury suffered by troops has increased dramatically, primarily from improvised explosive devices (IEDs), according to Martin Steele, Lieutenant General, U.S. Marine Corps (retired), USF associate vice president for veterans research, and executive director of Military Partnerships. In response, the U.S. Veterans Administration has increasingly focused on TBI research and treatment.

Dr. Cesar Borlongan (left), senior author, and Dr. Paul R. Sanberg, co-author

“Progressive injury to hippocampal, cortical and thalamic regions contributes to long-term cognitive damage post-TBI,” said study co-author Paul R. Sanberg,  PhD, DSc, USF senior vice president for research and innovation and executive director of the Center of Excellence for Aging and Brain Repair at USF Health. “Both military and civilian patients have shown functional and cognitive deficits resulting from TBI.”

Because TBI involves both acute and chronic stages, the researchers noted that animal model research on the chronic stages of TBI could provide insight into identifying therapeutic targets for treatment in the post-acute stage.

“Using animal models of TBI, our study investigated the prolonged pathological outcomes of TBI in different parts of the brain, such as the dorsal striatum, thalamus, corpus callosum white matter, hippocampus and cerebral peduncle,” said Dr. Borlongan, principal investigator for the study. “We found that a massive neuroinflammation after TBI causes a second wave of cell death that impairs cell proliferation and impedes the brain’s regenerative capabilities.”

 Upon examining rat brains eight weeks post-trauma, the researchers found “a significant up-regulation of activated microglia cells, not only in the area of direct trauma, but also in adjacent as well as distant areas.”  The location of inflammation correlated with the cell loss and impaired cell proliferation researchers observed.

Microglia cells act as the first and main form of immune defense in the central nervous system and make up 20 percent of the total glial cell population within the brain. They are distributed across large regions throughout the brain and spinal cord.

“Our study found that cell proliferation was significantly affected by a cascade of neuroinflammatory events in chronic TBI and we identified the susceptibility of newly formed cells within neurologic niches and suppression of neurological repair,” wrote the authors.

The researchers concluded that, while the progressive deterioration of the TBI-affected brain over time suppressed efforts of repair, intervention, even in the chronic stage of TBI injury, could help further deterioration.

The study was supported by the U.S. Department of Defense, the USF Signature Interdisciplinary Program in Neuroscience funds, the USF and Veterans Administration Reintegration Funds, and the USF Neuroscience Collaborative Program.

Citation:  Acosta SA, Tajiri N, Shinozuka K, Ishikawa H, Grimmig B, et al. (2013) Long-Term Upregulation of Inflammation and Suppression of Cell Proliferation in the Brain of Adult Rats Exposed to Traumatic Brain Injury Using the Controlled Cortical Impact Model. PLOS ONE 8(1): e53376. doi:10.1371/journal.pone.0053376

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The University of South Florida is a high-impact, global research university dedicated to student success. USF ranks 50th in the nation for federal expenditures in research and total expenditures in research among all U.S. universities, public or private, according to the National Science Foundation. Serving more than 47,000 students, the USF System has an annual budget of $1.5 billion and an annual economic impact of $3.7 billion. USF is a member of the Big East Athletic Conference.

News release by Randy Fillmore, special to USF Research News

Media contact:
Judy Lowry, USF Research & Innovation
813-974-3181, or jhlowry@usf.edu