and Prevention (CDC), yearly there are at least 1.7 million traumatic brain injury (TBI) cases reported either as an isolated injury or along with other injuries, and they contribute to almost one-third (30.5 percent) of all injury-related deaths in the United States. Each year about 52,000 deaths occur from traumatic brain injury. Approximately 75 percent of these TBIs are concussions or other forms of mild TBI. Nearly half a million emergency room visits for traumatic brain injuries are made each year by children aged 0 to 14 years, though the highest rates of TBI-related hospitalizations and deaths occur in adults aged 75 years and older.
The degree of the neurologic deficits instigated by a TBI lesion is determined by two main factors, which are the primary mechanical insult and the secondary insult caused by inflammation, compression, and ischemia. The primary lesion is produced by the trauma itself and involves cellular death and tissue necrosis, independently of the biological factors. The mechanisms underlying secondary lesions comprise activation of inflammation, tissue ischemia, reperfusion deficits, edema, lipid peroxidation, calcium influx, and principally apoptosis. These secondary lesions establish the main target for the development of novel therapeutic approaches like stem cell therapy.
In human beings, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the hippocampus dentate gyrus (DG) are the two major stem cell niches in the adult brain. Stem cells have the capability to induce neuroprotection, inflammatory suppression, and neural repair, allowing reconstruction of totally damaged tissues or inhibiting partially damaged cells from progressing to cell death. However, the neurological improvements observed in preclinical and clinical trials have been based on results of neurological and behavioral tests, while the underlying mechanism of action of stem cells remains unknown.
Research into stem cells is just beginning in the United States and when it comes to brain injury, stem cell therapy is in its infancy. Not many trials are being carried out in the United States regarding the use of stem cells for TBI, but those that are under way have shown some promise.
In a Phase I clinical trial carried out at the University of Texas Health Science Center at Houston (UTHealth), bone marrow stem cells (BMSC) that were derived from the patient’s own bone marrow were safely used in pediatric patients with acute TBI. This clinical trial included 10 children aged 5 to 14 years with severe TBI and was carried out in partnership with Children’s Memorial Hermann Hospital, which is UTHealth’s primary children’s teaching hospital. All the children enrolled in this trial were treated acutely within 48 hours of their injury with their own stem cells collected from their bone marrow. These bone marrow stem cells were processed and administered intravenously to the children.
According to the data put forward by UTHealth, the acute harvesting of bone marrow and infusion of bone marrow mononuclear cells to acutely treat severe TBI in children is safe. As this was a Phase I trial to look at feasibility and safety of the method, this study did not evaluate the efficacy. Nonetheless, after six months of follow-up, all of the children had significant improvement, and seven of the 10 children revealed good outcome, displaying no or only mild disability.
In 2011, UTHealth began enrollment for the first Phase I safety study approved by the U.S. Food and Drug Administration (FDA) to investigate the use of a child’s own umbilical cord blood stem cells for traumatic brain injury in children. The study is being performed in conjunction with Children’s Memorial Hermann Hospital and Cord Blood Registry Center for Regenerative Medicine (Cord Blood Registry, or CBR), which is known to be the world’s largest and most experienced stem cell bank. The trial will enroll 10 children ages 18 months to 17 years who have umbilical cord blood banked with CBR and have suffered moderate to severe TBI. This study is not designed for acute care and will only enroll participants within 6–18 months of their injury.
In order to enroll in the study, parents or caregivers of patients who have suffered a traumatic brain injury should contact CBR and after consent is obtained, the information will be relayed to the UTHealth research group. CBR helps by connecting the child and family with appropriate researchers and thus plays a significant role in the study. If all qualifications are met, the patient will travel to Children’s Memorial Hermann Hospital. The cells will be processed and intravenously infused. Patients will be followed at six months, one year, and two years. This study is considered to be the forefront of researches evaluating a juvenile’s own cord blood stem cells’ ability to help the healing process after TBI-induced damage to nerve tissue in the brain.
Three Theories Defining How Stem Cells Work in TBI
Up till now, there have been two widely held opinions on how stem cells can work to provide potential treatments for brain damage caused by injury or neurodegenerative disorders. One doctrine is that stem cells implanted into the site of injured brain tissue directly replace dead or dying cells. The other, more current view is that transplanted stem cells secrete growth factors that indirectly save the injured tissue.
In late 2013, University of South Florida (USF) researchers presented evidence for a third theory of stem cell mediated brain repair following trauma. In a series of preclinical experiments under principal investigator Professor Cesar Borlongan, who is also the director of the USF Center for Aging and Brain Repair, the team reported that transplanted stem cells appear to build a “biobridge” that links an undamaged intact brain site where new neural stem cells are born with the damaged injured region of the brain. According to the USF rsearchers, the transplanted stem cells serve as migratory signals for the brain’s own neurogenic cells, guiding the migration of these newly formed host cells from their neurogenic niche toward the injured brain tissue.
The researchers at USF indiscriminately assigned rats with TBI and confirmed neurological impairment to one of two groups. One group received transplants of SanBio Inc.’s bone marrow–derived stem cells (SB632 cells) into the region of the brain affected by traumatic injury. The other control group received a replica procedure in which solution alone was infused into the brain with no implantation of stem cells.
At one and three months post-TBI follow-up, the rats receiving stem cell transplants displayed considerably better motor and neurological function and reduced brain tissue damage compared to the control group rats receiving solution alone. These healthy improvements were observed even though the survival of the transplanted cells was modest and reduced over time.
The researchers then conducted a series of experiments to examine the host rats’ brain tissue. At three months post TBI, the brains of the rats transplanted with stem cells showed substantial cell proliferation and differentiation of stem cells into neuron-like cells in the area of injury. This was accompanied by a solid stream of stem cells migrating from the brain’s uninjured subventricular zone (SVZ), one of the two major stem cell niches in the brain, as described above, to the brain’s site of injury.
On the other hand, the rats receiving solution alone showed restricted proliferation and neural commitment of stem cells, with only dispersed migration to the site of brain injury and virtually no expression of newly formed cells in the SVZ. Without the addition of transplanted stem cells, the brain’s self-repair process appeared inadequately deficient to maintain a defense against the cascade of TBI-induced cell death. Based on the data reported by the USF researchers in this preclinical study, the FDA recently approved a limited clinical trial to transplant SB632 cells (an adult stem cell therapy) prepared by SanBio Inc. into patients with traumatic brain injury.
Syed A. Quadri
Desert Regional Medical Center, Palm Springs
Mudassir Farooqui
Aga Khan University Hospital
Atif Zafar
University of Iowa Hospitals and Clinics
Fahad
