Umbilical cord cell and growth factor treatment tested in animal models could offer hope for millions, including U.S. war veterans with traumatic brain injuries

USF Health neuroscientist Cesar Borlongan, PhD, the study’s lead author.

Tampa, FL (March 20, 2014) — Traumatic brain injuries (TBI), sustained by close to 2 million Americans annually, including military personnel, are debilitating and devastating for patients and their families. Regardless of severity, those with TBI can suffer a range of motor, behavioral, intellectual and cognitive disabilities over the short or long term. Sadly, clinical treatments for TBI are few and largely ineffective.

In an effort to find an effective therapy, neuroscientists at the Center of Excellence for Aging and Brain Repair, Department of Neurosurgery in the USF Health Morsani College of Medicine, University of South Florida, have conducted several preclinical studies aimed at finding combination therapies to improve TBI outcomes.

In their study of several different therapies—alone and in combination—applied to laboratory rats modeled with TBI, the USF researchers found that a combination of human umbilical cord blood cells (hUBCs) and granulocyte colony stimulating factor (G-CSF), a growth factor, was more therapeutic than either administered alone, or each with saline, or saline alone.

The study appeared in a recent issue of PLoS ONE.

“Our results showed that the combined therapy of hUBCs and G-CSF significantly reduced the TBI-induced loss of neuronal cells in the hippocampus,” said study lead author Cesar V. Borlongan, PhD, professor of neurosurgery and director of USF’s Center of Excellence for Aging and Brain Repair. “Therapy with hUBCs and G-CSF alone or in combination produced beneficial results in animals with experimental TBI. G-CSF alone produced only short-lived benefits, while hUBCs alone afforded more robust and stable improvements. However, their combination offered the best motor improvement in the laboratory animals.”

For full story, go to: http://www.research.usf.edu/absolute-news/templates/template1.aspx?articleid=2106&zoneid=1

University of South Florida researchers have suggested a new view of how stem cells may help repair the brain following trauma. In a series of preclinical experiments, they report that transplanted cells appear to build a “biobridge” that links an uninjured brain site where new neural stem cells are born with the damaged region of the brain.

Their findings were recently reported online in the peer-reviewed journal PLOS ONE.

“The transplanted stem cells serve as migratory cues for the brain’s own neurogenic cells, guiding the exodus of these newly formed host cells from their neurogenic niche towards the injured brain tissue,” said principal investigator Cesar Borlongan, PhD, professor and director of the USF Center for Aging and Brain Repair.

A team led by Cesar Borlongan, director of the University of South Florida Center for Aging and Brain Repair, offers a new concept for how transplanted stem cells help prod the brain’s own repair mechanism following traumatic brain injury.

Based in part on the data reported by the USF researchers in this preclinical study, the U.S. Food and Drug Administration recently approved a limited clinical trial to transplant SanBio Inc’s SB632 cells (an adult stem cell therapy) in patients with traumatic brain injury.

Stem cells are undifferentiated, or blank, cells with the potential to give rise to many different cell types that carry out different functions. While the stem cells in adult bone marrow or umbilical cord blood tend to develop into the cells that make up the organ system from which they originated, these multipotent stem cells can be manipulated to take on the characteristics of neural cells.

To date, there have been two widely-held views on how stem cells may work to provide potential treatments for brain damage caused by injury or neurodegenerative disorders.  One school of thought is that stem cells implanted into the brain directly replace dead or dying cells.  The other, more recent view is that transplanted stem cells secrete growth factors that indirectly rescue the injured tissue.

The USF study presents evidence for a third concept of stem-cell mediated brain repair.

The researchers randomly assigned rats with traumatic brain injury and confirmed neurological impairment to one of two groups. One group received transplants of bone marrow-derived stem cells (SB632 cells) into the region of the brain affected by traumatic injury. The other (control group) received a sham procedure in which solution alone was infused into the brain with no implantation of stem cells.

At one and three months post-TBI, the rats receiving stem cell transplants showed significantly better motor and neurological function and reduced brain tissue damage compared to rats receiving no stem cells. These robust improvements were observed even though survival of the transplanted cells was modest and diminished over time.

The researchers then conducted a series of experiments to examine the host brain tissue.

At three months post-traumatic brain injury, the brains of transplanted rats showed massive cell proliferation and differentiation of stem cells into neuron-like cells in the area of injury, the researchers found. This was accompanied by a solid stream of stem cells migrating from the brain’s uninjured subventricular zone — a region where many new stem cells are formed – to the brain’s site of injury.

In contrast, the rats receiving solution alone showed limited proliferation and neural-commitment of stem cells, with only scattered migration to the site of brain injury and virtually no expression of newly formed cells in the subventricular zone. Without the addition of transplanted stem cells, the brain’s self-repair process appeared insufficient to mount a defense against the cascade of traumatic brain injury-induced cell death.

The researchers conclude that the transplanted stem cells create a neurovascular matrix that bridges the long-distance gap between the region in the brain where host neural stem cells arise and the site of injury. This pathway, or “biobridge,” ferries the newly emerging host cells to the specific place in the brain in need of repair, helping promote functional recovery from traumatic brain injury.

Article citation:
“Stem Cell Recruitment of Newly Formed Host Cells via a Successful Seduction? Filling the Gap between Neurogenic Niche and Injured Brain Site;”  Naoki Tajiri, Yuji Kaneko, Kazutaka Shinozuka, Hiroto Ishikawa, Ernest Yankee, Michael McGrogan, Casey Case, and Cesar V. Borlongan; PLOS ONE 8(9): e74857.  Published Sept. 4, 2013.

Findings suggest that blood-brain barrier integrity suffers days after ischemic stroke, leading to serious complications; repair of this protective barrier might prevent them

Tampa, FL (May 20, 2013) — While the effects of acute stroke have been widely studied, brain damage during the subacute phase of stroke has been a neglected area of research. Now, a new study by the University of South Florida  reports that within a week of a stroke caused by a blood clot in one side of the brain, the opposite side of the brain shows signs of microvascular injury.  

Stroke is a leading cause of death and disability in the United States, and increases the risk for dementia.

 “Approximately 80 percent of strokes are ischemic strokes, in which the blood supply to the brain is restricted, causing a shortage of oxygen,” said study lead author Svitlana Garbuzova-Davis, PhD, associate professor in the USF Department of Neurosurgery and Brain Repair. “Minutes after ischemic stroke, there are serious effects within the brain at both the molecular and cellular levels.  One understudied aspect has been the effect of ischemic stroke on the competence of the blood-brain barrier and subsequent related events in remote brain areas.”

USF Health neuroscientist Svitlana Garbuzova-Davis, PhD, was lead author of the study.

Using a rat model, researchers at USF Health investigated the subacute phase of ischemic stroke and found deficits in the microvascular integrity in the brain hemisphere opposite to where the initial stroke injury occured.

The study was published in the May 10, 2013 issue of PLOS One.

The USF team found that “diachisis,” a term used to describe certain brain deficits remote from primary insult, can occur during the subacute phase of ischemic stroke. The research discovered diachisis is closely related to a breakdown of the blood-brain barrier, which separates circulating blood from brain tissue.

In the subacute phase of an ischemic stroke, when the stroke-induced disturbances in the brain occur in remote brain microvessels, several areas of the brain are affected by a variety of injuries, including neuronal swelling and diminished myelin in brain structures. The researchers suggest that recognizing the significance of microvascular damage could make the blood-brain barrier (BBB) a therapeutic “target” for future neuroprotective strategies for stroke patients.

The mechanisms of BBB permeability at different phases of stroke are poorly understood.  While there have been investigations of BBB integrity and processes in ischemic stroke, the researchers said, most examinations have been limited to the phase immediately after stroke, known as acute stroke.  Their interest was in determining microvascular integrity in the brain hemisphere opposite to an initial stroke injury at the subacute phase.

Accordingly, this study using rats with surgically-simulated strokes was designed to investigate the effect of ischemic stroke on the BBB in the subacute phase, and the effects of a compromised BBB upon various brain regions, some distant from the stroke site.

“The aim of this study was to characterize subacute diachisis in rats modeled with ischemic stroke,” said co-author Cesar Borlongan, PhD, professor and vice chairman for research in the Department of Neurosurgery and Brain Repair and director of the USF Center for Aging and Brain Repair.  “Our specific focus was on analyzing the condition of the BBB and the processes in the areas of the brain not directly affected by ischemia. BBB competence in subacute diachisis is uncertain and needed to be studied.”

Their findings suggest that damage to the BBB, and subsequent vascular leakage as the BBB becomes more permeable, plays a major role in subacute diachisis. 

The increasing BBB permeability hours after the simulated stroke, and finding that the BBB “remained open” seven days post-stroke, were significant findings, said Dr. Garbuzova-Davis, who is also a researcher in USF Center for Aging and Brain Repair. “Since increased BBB permeability is often associated with brain swelling, BBB leakage may be a serious and life-threatening complication of ischemic stroke.”

Another significant aspect was the finding that autophagy — a mechanism involving cell degradation of unnecessary or dysfunctional cellular components —plays a role in the subacute phase of ischemia.  Study results showed that accumulation of numerous autophagosomes within endothelial cells in microvessels of both initially damaged and non-injured brain areas might be closely associated with BBB damage.  Autophagy is a complex but normal process usually aimed at “self-removing” damaged cell components to promote cell survival. It was unclear, however, whether the role of autophagy in subacute post-ischemia was promoting cell survival or cell death.

More than 30 percent of patients who survive strokes develop dementia within two years, the researchers noted.

“Although dementia is complex, vascular damage in post-stroke patients is a significant risk factor, depending on the severity, volume and site of the stroke,” said study co-author Dr. Paul Sanberg, USF senior vice president for research and innovation. “Ischemic stroke might initiate neurodegenerative dementia, particularly in the aging population.”

The researchers conclude that repair of the BBB following ischemic stroke could potentially prevent further degradation of surviving neurons.

“Recognizing that the BBB is a therapeutic target is important for developing neuroprotective strategies,” they said.

In addition to researchers from USF, researchers from the Ribeirao Preto School of Medicine, University of Sao Paulo, Sao Paulo, Brazil, contributed to the study.

The study was supported by the National Institutes of Health (1RO1NS071956-01A1) and the James and Esther King Biomedical Research Program (1KG01-33966).

# # #

The Department of Neurosurgery and Brain Repair has strong and ongoing commitments to  neurosurgical education both at the residency and fellowship level and also to providing ongoing educational efforts for practicing physicians. Multiple avenues of research under investigation in the department include conducting clinical research in the fields of complex spinal disorders, epilepsy, brain tumor treatment, and stroke care, among others. In the departmental laboratories, studies of spinal biomechanics, neurodegenerative disorders, and microsurgical techniques are also underway. We are trying to improve the treatments available for our neurosurgical patients and neurological patients throughout the world. http://health.usf.edu/medicine/neurosurgery/index.htm

# # #

The mission of the Center of Excellence for Aging and Brain Repair is to develop new therapeutic strategies to promote repair and regeneration of aging and diseased brain. Building on a foundation of excellence in basic and clinical research, the center focuses on translating innovative ideas into industrial partnerships and educational and clinical services to address key needs of the community and those suffering from brain injury and disease. http://health.usf.edu/nocms/medicine/neurosurgery/ceabr/

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

– About USF – 

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

USF among top 10 organizations worldwide with 15 Fellows named this year

USF Health researchers comprised a third (5) of the record number of University of South Florida faculty members elected 2012 Fellows of the American Association for the Advancement of Science (AAAS). 

The 15 faculty members from USF awarded the prestigious honor — up from four last year – catapulted USF into the top 10 institutions worldwide with the most AAS Fellows named this year.  The lifetime designation recognizes scientifically or socially distinguished efforts to advance science or its applications.

The five USF Health faculty members – representing the Morsani College of Medicine, College of Public Health and College of Pharmacy – named AAAS Fellows this year are:

Paula C. Bickford, PhD, professor of Neurosurgery and Brain Repair and senior research career scientist at James A. Haley Veterans’ Hospital:  For distinguished contributions to the field of aging research, and particularly as a leader in the field of nutritional neuroscience and for outstanding service.

Cesar V. Borlongan, PhD, professor and vice chair for research in Neurosurgery and Brain Repair:   For distinguished contributions to the field of stem cell therapy for neurological disorders, particularly for advancing translational biomedical research of cell based-therapeutics in stroke.

Robert J. Deschenes, PhD, professor and chair of Molecular Medicine:  For distinguished contributions to the field of molecular cell biology and the use of model genetic systems to elucidate the spatial arrangement of signaling proteins. 

Karen D. Liller, PhD, professor of Community and Family Health, dean of the USF Graduate School, and associate vice president for Research and Innovation:  For distinguished contributions as a graduate education administrator and also as a research scholar in the fields of public health and children’s injury prevention.

Lynn Wecker, PhD, Distinguished University Professor of Psychiatry and Behavioral Neuroscience and Distinguished Research Professor:   For distinguished service to the scientific community as an innovative, highly accomplished researcher, award-winning teacher, and dedicated servant and leader of her academic disciplines.

For more  information, go to the USF News Page.

Five of the record-breaking 15 faculty members from USF named 2012 AAAS Fellows are from USF Health.