Stem Cell Therapy Might Improve Brain Function of Traumatic Brains Injury Patients


Accidents happen and sometimes really bad accidents happen; especially if they injure your head.  Traumatic brain injuries or TBIs can result from automobile accidents, explosions or other events that result from severe blows to the head.  TBIs  an adversely affect a patient and his/her family for long periods of time.  TBI patients can experience cognitive deficits that prevent them from thinking or speaking straight, and sensory deficits that prevent them from seeing, hearing or smelling properly.  Psychological problems can also result.  Essentially, TBIs represent a major challenge for modern medicine.

According to data from the Centers for Disease Control (CDC), 1.7 million Americans suffer from TBIs each year (of varying severity).  Of these, 275,000 are hospitalized for their injuries and approximately 52,000 of these patients die from their injuries.  In fact, TBIs contribute to one-third of all injury-related deaths in the United States each year.  More than 6.5 million patients are burdened by the deleterious effects of TBIs, and this leads to an economic burden of approximately $60 billion each year.

Currently, treatments for TBI are few and far between.  Neurosurgeons can use surgery to repair damaged blood vessels and tissues, and diminish swelling in the brain.  Beyond these rather invasive techniques, the options for clinicians are poor.

A new study by Charles S. Cox, professor of Pediatric Surgery and co-director of the Memorial Hermann Red Duke Trauma Institute, and his colleagues suggest that stem cell treatments might benefit TBI patients.  The results of this study were published in the journal Stem Cells.

This study enrolled 25 TBI patients.  Five of them received no treatment and served as controls, but the remaining 20 received gradually increasing dosages of their own bone marrow stem cells.  The harvesting, processing and infusion of the bone marrow cells occurred within 48 hours of injury.  Functional and cognitive results were measured with standard tests and brain imaging with magnetic resonance imaging and diffusion tensor imaging.

This work is an extension of extensive preclinical work done by Cox and his coworkers in laboratory animals and a phase I study that established that such stem cell transplantation are safe for human patients.  The implanted stem cells seem to quell brain inflammation and lessen the damage to the brain by the TBI.

Despite the fact that those TBI patients who received the stem cell treatments had greater degrees of brain damage, the treatment group showed better structural preservation of the brain and better functional outcomes than the control group.  Of particular interest was the decrease in indicators of inflammation as a result of the bone marrow cell-based infusions.

Cox said of this trial, “The data derived from this trial moves beyond just testing safety of this approach.”  He continued:  “We now have a hint of a treatment effect that mirrors our pre-clinical work, and were are now pursuing this approach in a phase IIb clinical trial sponsored by the Joint Warfighter Program within the US Army Medical Research Acquisition Activity, as well as our ongoing phase IIb pediatric severe TBI clinical trial; both using the same autonomous cell therapy.”

This an exciting study, but it is a small study.  While the safety of this procedure has been established, the precise dosage and long-term benefits will require further examination.  However it is a fine start to what may become the flowering of new strategies to treat TBI patients.

Umbilical Cord Blood Cells Combined with Growth Factors Improves Traumatic Brain Injury Outcomes


Approximately 2 million Americans experience a traumatic brain injury every year. Most of these are individuals who employed in high-risk jobs such as the military, firefighting, police work and others types of essential but highly dangerous jobs. No matter how small the injury, individuals who have suffered a traumatic brain injury (TBI) can suffer from a whole host of motor, behavioral, intellectual and cognitive disabilities over the short or long-term. Unfortunately, there are few clinical treatments for TBI, and the few we have are rather ineffective.

In order to design better, more effective treatments for TBI, 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 used umbilical cord stem cells in combination with growth factors to treat TBIs in mice.

This study investigated the ability of several strategies, both by themselves and in combination with other therapies, to treat rats with a laboratory form of TBI. In particular, the USF team discovered 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.

“Chronic TBI is typically associated with major secondary molecular injuries, including chronic neuroinflammation, which not only contribute to the death of neuronal cells in the central nervous system, but also impede any natural repair mechanism,” said study lead author Cesar V. Borlongan, PhD, professor of neurosurgery and director of USF’s Center of Excellence for Aging and Brain Repair. “In our study, we used hUBCs and G-CSF alone and in combination. In previous studies, hUBCs have been shown to suppress inflammation, and G-CSF is currently being investigated as a potential therapeutic agent for patients with stroke or Alzheimer’s disease.”

In previous studies, Borlongan and his team showed that G-CSF can mobilize stem cells from bone marrow and induce them to home to and infiltrate injured tissues. While there, the cells promote neural cell self-repair. Cells from human umbilical cord blood also have the ability to suppress inflammation and promote cell growth.

“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 Borlongan. “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.”

“This outcome may indicate that the stem cells had more widespread biological action than the drug therapy,” said Paul R. Sanberg, distinguished professor at USF and principal investigator of the Department of Defense funded project. “Regardless, their combination had an apparent synergistic effect and resulted in the most effective amelioration of TBI-induced behavioral deficits.”

This particular study examined motor improvements or improvements in movement, but the USF group suggested that future combination therapy research should also include analysis of cognitive improvement in the laboratory animals with TBI.

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

Post-script:  On Twitter, Alexey Bersenev made some very helpful observations about this paper.  In this paper, the authors used whole human umbilical cord blood.  They did not attempt to separate any of the different cell types from the cord blood.  Now when such whole blood is used, it is easy to assume that the stem cells in the blood that are doing the regenerative work.  However, as Alexey graciously pointed out, you cannot assume that the stem cells are responsible for the therapeutic effects for at least two main reasons:  1)  the number of stem cells in the cord blood is quite small relative to the other cells; 2) some of the non-stem cells in the blood turn out to have therapeutic effects.  See here and here.  I have seen some of these papers before, but I did not think much of them.  Therefore, until the cell populations in the umbilical cord blood are dissected out and studied, all we can say with any confidence is SOMETHING in the cord blood is conveying a therapeutic effect, but the identity of the therapeutic culprit remains unclear at this time.

TIMP3 Secreted by Mesenchymal Stem Cells Protects the Blood Brain Barrier After a Traumatic Brain Injury


Mesenchymal stem cells (MSCs) are found in multiple tissues and locations throughout our bodies, and they have the ability to differentiate into bone, fat, cartilage, and smooth muscle. MSCs also have the ability to suppress unwanted immune responses and inflammation. Therefore, MSCs are prime candidates for regenerative medical treatments.

MSCs have been used to experimentally treat traumatic brain injury (for example, Galindo LT et al., Neurol Res Int 2011;2011:564089). One of the main concerns after traumatic brain injury is damage to the blood brain barrier (BBB). BBB damage allows inflammatory cells to access the brain and further damage it. Therefore, healing the damage to the BBB or protecting the BBB after a traumatic brain injury is vital to the brain after a traumatic brain injury.

After a traumatic brain injury, the vascular system suffers damage and begins to leak. When blood leaks into tissues, it tends to irritate the tissues and damage them. MSCs release a soluble factor known as TIMP3 (tissue metalloproteinase-3) that degrades blood-based proteins known to cause damage to tissues when blood vessels leak. TIMP3 production by MSCs can also protect the BBB from degradation after a traumatic brain injury.

Researchers from the University of Texas Health Sciences Center, UC San Francisco, and two biotechnology companies have examined the protective role of MSCs and one particular protein secreted by MSCs in protecting the BBB after traumatic brain injury.

Shibani Pati, from UC San Francisco, and his collaborators from the University of Texas, Houston, MD Anderson Cancer Center, Amgen, and Blood Systems Research Institute (San Francisco) used MSCs to staunch the increased permeability the BBB after a traumatic brain injury.

They used a mouse model in these experiments and induced traumatic brain injuries in these mice. Then they gave MSCs to some, and soluble TIMP3 to others, and buffer to another group as a control. They discovered that the MSCs mitigated BBB damage after a traumatic brain injury. However, they also found that soluble TIMP3 could also protect the BBB approximately as well as MSCs. This suggested that the TIMP3 secretion by MSCs is the main mechanism by which MSCs protect the BBB after a traumatic brain injury.

To test this hypothesis, Pati and his colleagues administered MSCs to mice that had experienced traumatic brain injury, but they also co-administered a soluble inhibitor to TIMP3. They discovered that this inhibitor completely abolished the ability of MSCs to protect the BBB after a traumatic brain injury. They also found that the main target of TIMP3 was vascular endothelial growth factor. Apparently after a traumatic brain injury, massive release of vascular endothelial growth factor causes the breakdown of BBB structures. TIMP3 degrades vascular endothelial growth factor, which prevents BBB breakdown.

These findings suggest that administration of recombinant proteins such as TIMP3 after a traumatic brain injury can protect the BBB and decrease brain damage. Clinical trial anyone?

Stem Cell Transplant into the Carotid Artery Shows Promise as Treatment for Traumatic Brain Injury


The injection of stem cells into the carotid artery of brain-injured rats allows the stem cells to move directly to the brain where they greatly enhance brain repair and healing, speeding functional neurological recovery.

This stem cell injection technique was combined with imaging to track the injected stem cells after their introduction into the animal. This study is part of a larger project to study the feasibility of stem cell treatments for traumatic brain injury (TBI) in humans. This research group is being led by Dr. Toshiya Osanai of Hokkaido University Graduate School of Medicine, Sapporo, Japan.

In this experiment, traumatic brain injuries were induced in laboratory rats, and seven days later, bone marrow stem cells were isolated and injected into the carotid arteries. Since injections directly into the brain are dangerous and can cause further brain damage, a technique that places stem cells into the peripheral circulation is preferable. However, many animal and clinical studies have shown that stem cells placed into the peripheral circulation tend to get stuck in the lungs, spleen, liver, and other places. For example, Wang W, et al Cell Transplant 2010;19(12):1599-1607 injected bone marrow mesenchymal stem cells into the heart of rats that had recently experienced a heart attack, and found the many of the injected stem cells stayed in the heart, but many others spread to the lungs, spleen, and lungs. This finding has been confirmed by several other studies as well (Zhang H, et al J Thorac Cardiovasc Surg. 2007;134(5):1234-40 & Wang W, et al, Regen Med. 2011;6(2):179-90). Therefore, Osanai’s research group decided to inject stem cells into the blood vessels that directly feed the brain. This way, the stem cells should find their way to the brain without getting lost in general circulation.

Before injection, the bone marrow stem cells were labeled with “quantum dots,” which are a biocompatible, fluorescent semiconductor created using nanotechnology. The quantum dots emit near-infrared light. Near-infrared light has very long wavelengths that penetrate bone and skin, which allowed the researchers to noninvasively monitor the stem cells for four weeks after transplantation.

Using this in vivo combination of optical imaging and carotid injection, Osanai and colleagues observed the bone marrow-derived stem cells enter the brain on the “first pass,” without entering general circulation. Within three hours, the stem cells began to migrate from the smallest brain blood vessels (capillaries) into the area of brain injury.

After four weeks, rats treated with stem cells showed significant recovery of motor function (movement), while untreated rats showed no such recovery. Examination of the treated brains confirmed that the stem cells had transformed into different types of brain cells and participated in healing of the injured brain area.

Stem cells from bone marrow are likely to become an important new treatment for patients with traumatic brain injuries and stroke. Bone marrow stem cells, like the ones used in this study, are a promising source of donor cells. However, despite the many questions that remain regarding the optimal timing, dose, and route of stem cell delivery.

In the new animal experiments, stem cell transplantation was performed one week after a traumatic brain injury, which is a “clinically relevant” time, since it takes at least that long to develop stem cells from bone marrow. Injecting such stem cells into the carotid artery is a relatively simple procedure that delivers the cells directly to the brain.

These experiments also add to the evidence that stem cell treatment can promote healing after traumatic brain injury, with significant recovery of function. Osanai and colleagues wrote that, with the use of in vivo optical imaging, “The present study was the first to successfully track donor cells that were intra-arterially transplanted into the brain of living animals over four weeks.”

Some similar form of imaging technology might be useful in monitoring the effects of stem cell transplantation in humans.  However, tracking stem cells in human patients will pose challenges, as the skull and scalp are much thicker in humans than in rats.  Clearly further studies are warranted to apply in vivo optical imaging clinically.