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Mesenchymal Stem Cells in the Treatment of Traumatic Brain Injury.

ABSTRACT: Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. The primary insult to the brain initiates secondary injury cascades consisting of multiple complex biochemical responses of the brain that significantly influence the overall severity of the brain damage and clinical sequelae. The use of mesenchymal stem cells (MSCs) offers huge potential for application in the treatment of TBI. MSCs have immunosuppressive properties that reduce inflammation in injured tissue. As such, they could be used to modulate the secondary mechanisms of injury and halt the progression of the secondary insult in the brain after injury. Particularly, MSCs are capable of secreting growth factors that facilitate the regrowth of neurons in the brain. The relative abundance of harvest sources of MSCs also makes them particularly appealing. Recently, numerous studies have investigated the effects of infusion of MSCs into animal models of TBI. The results have shown significant improvement in the motor function of the damaged brain tissues. In this review, we summarize the recent advances in the application of MSCs in the treatment of TBI. The review starts with a brief introduction of the pathophysiology of TBI, followed by the biology of MSCs, and the application of MSCs in TBI treatment. The challenges associated with the application of MSCs in the treatment of TBI and strategies to address those challenges in the future have also been discussed.

SUBMITTER: Hasan A

PROVIDER: S-EPMC5316525 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Mesenchymal Stem Cells in the Treatment of Traumatic Brain Injury.

Hasan Anwarul A Deeb George G Rahal Rahaf R Atwi Khairallah K Mondello Stefania S Marei Hany Elsayed HE Gali Amr A Sleiman Eliana E

Frontiers in neurology 20170220

Traumatic brain injury (TBI) is characterized by a disruption in the normal function of the brain due to an injury following a trauma, which can potentially cause severe physical, cognitive, and emotional impairment. The primary insult to the brain initiates secondary injury cascades consisting of multiple complex biochemical responses of the brain that significantly influence the overall severity of the brain damage and clinical sequelae. The use of mesenchymal stem cells (MSCs) offers huge pot ...[more]

PMID: 28265255

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Project description:Combinations of biomaterials and cells can effectively target delivery of cells or other therapeutic factors to the brain to rebuild damaged nerve pathways after brain injury. Porous collagen-chitosan scaffolds were prepared by a freeze-drying method based on brain tissue engineering. The scaffolds were impregnated with rat bone marrow mesenchymal stem cells. A traumatic brain injury rat model was established using the 300 g weight free fall impact method. Bone marrow mesenchymal stem cells/collagen-chitosan scaffolds were implanted into the injured brain. Modified neurological severity scores were used to assess the recovery of neurological function. The Morris water maze was employed to determine spatial learning and memory abilities. Hematoxylin-eosin staining was performed to measure pathological changes in brain tissue. Immunohistochemistry was performed for vascular endothelial growth factor and for 5-bromo-2-deoxyuridine (BrdU)/neuron specific enolase and BrdU/glial fibrillary acidic protein. Our results demonstrated that the transplantation of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds to traumatic brain injury rats remarkably reduced modified neurological severity scores, shortened the average latency of the Morris water maze, increased the number of platform crossings, diminished the degeneration of damaged brain tissue, and increased the positive reaction of vascular endothelial growth factor in the transplantation and surrounding areas. At 14 days after transplantation, increased BrdU/glial fibrillary acidic protein expression and decreased BrdU/neuron specific enolase expression were observed in bone marrow mesenchymal stem cells in the injured area. The therapeutic effect of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds was superior to stereotactic injection of bone marrow mesenchymal stem cells alone. To test the biocompatibility and immunogenicity of bone marrow mesenchymal stem cells and collagen-chitosan scaffolds, immunosuppressive cyclosporine was intravenously injected 12 hours before transplantation and 1-5 days after transplantation. The above indicators were similar to those of rats treated with bone marrow mesenchymal stem cells and collagen-chitosan scaffolds only. These findings indicate that transplantation of bone marrow mesenchymal stem cells in a collagen-chitosan scaffold can promote the recovery of neuropathological injury in rats with traumatic brain injury. This approach has the potential to be developed as a treatment for traumatic brain injury in humans. All experimental procedures were approved by the Institutional Animal Investigation Committee of Capital Medical University, China (approval No. AEEI-2015-035) in December 2015.

Project description:More than 6.5 million patients are burdened by the physical, cognitive, and psychosocial deficits associated with traumatic brain injury (TBI) in the U.S. Despite extensive efforts to develop neuroprotective therapies for this devastating disorder, there have been no successful outcomes in human clinical trials to date. Retrospective studies have shown that ?-adrenergic receptor blockers, specifically propranolol, significantly decrease mortality of TBI through mechanisms not yet fully elucidated but are thought to counterbalance a hyperadrenergic state resulting from a TBI. Conversely, cellular therapies have been shown to improve long-term behavior following TBI, likely by reducing inflammation. Given the nonredundancy in their therapeutic mechanisms, we hypothesized that a combination of acute propranolol followed by mesenchymal stem cells (MSCs) isolated from human bone marrow would have additive effects in treating a rodent model of TBI. We have found that the treatments are well-tolerated individually and in combination with no adverse events. MSCs decrease BBB permeability at 96 hours after injury, inhibit a significant accumulation of activated microglia/macrophage in the thalamic region of the brain both short and long term, and enhance neurogenesis short term. Propranolol decreases edema and reduces the number of fully activated microglia at 7 days and the number of semiactivated microglia at 120 days. Combinatory treatment improved cognitive and memory functions 120 days following TBI. Therefore, the results here suggest a new, efficacious sequential treatment for TBI may be achieved using the ?-blocker propranolol followed by MSC treatment.Despite continuous efforts, traumatic brain injury (TBI) remains the leading cause of death and disability worldwide in patients under the age of 44. In this study, an animal model of moderate-severe TBI was treated with an acute dose of propranolol followed by a delayed dose of human mesenchymal stem cells (MSCs), resulting in improved short- and long-term measurements. These results have direct translational application. They reinforce the inevitable clinical trial of MSCs to treat TBI by demonstrating, among other benefits, a notable decrease in chronic neuroinflammation. More importantly, these results demonstrate that MSCs and propranolol, which is increasingly being used clinically for TBI, are compatible treatments that improve overall outcome.

Project description:BackgroundStudies have shown that transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) protects against brain damage. However, the low survival number of transplanted BMSCs remains a pertinent challenge and can be attributed to the unfavorable microenvironment of the injured brain. It is well known that calpain activation plays a critical role in traumatic brain injury (TBI)-mediated inflammation and cell death; previous studies showed that inhibiting calpain activation is neuroprotective after TBI. Thus, we investigated whether preconditioning with the calpain inhibitor, MDL28170, could enhance the survival of BMSCs transplanted at 24 h post TBI to improve neurological function.MethodsTBI rat model was induced by the weight-drop method, using the gravitational forces of a free falling weight to produce a focal brain injury. MDL28170 was injected intracranially at the lesion site at 30 min post TBI, and the secretion levels of neuroinflammatory factors were assessed 24 h later. BMSCs labeled with green fluorescent protein (GFP) were locally administrated into the lesion site of TBI rat brains at 24 h post TBI. Immunofluorescence and histopathology were performed to evaluate the BMSC survival and the TBI lesion volume. Modified neurological severity scores were chosen to evaluate the functional recovery. The potential mechanisms by which MDL28170 is involved in the regulation of inflammation signaling pathway and cell apoptosis were determined by western blot and immunofluorescence staining.ResultsOverall, we found that a single dose of MDL28170 at acute phase of TBI improved the microenvironment by inhibiting the inflammation, facilitated the survival of grafted GFP-BMSCs, and reduced the grafted cell apoptosis, leading to the reduction of lesion cavity. Furthermore, a significant neurological function improvement was observed when BMSCs were transplanted into a MDL28170-preconditioned TBI brains compared with the one without MDL28170-precondition group.ConclusionsTaken together, our data suggest that MDL28170 improves BMSC transplantation microenvironment and enhances the neurological function restoration after TBI via increased survival rate of BMSCs. We suggest that the calpain inhibitor, MDL28170, could be pursued as a new combination therapeutic strategy to advance the effects of transplanted BMSCs in cell-based regenerative medicine.

Project description:Preclinical studies using bone marrow derived cells to treat traumatic brain injury have demonstrated efficacy in terms of blood-brain barrier preservation, neurogenesis, and functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe traumatic brain injury demonstrated safety and potentially a central nervous system structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Adults with severe traumatic brain injury (Glasgow Coma Scale 5-8) and without signs of irreversible brain injury were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6, 9, 12 ×106 cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest-related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included magnetic resonance imaging-based measurements of supratentorial and corpus callosal volumes as well as diffusion tensor imaging-based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months postinjury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pretreatment, posttreatment, and at 1 and 6 month follow-up. There were no serious adverse events. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes. Key inflammatory cytokines were downregulated. Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by central nervous system structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are downregulated after cell infusion. Stem Cells 2016 Video Highlight: https://youtu.be/UiCCPIe-IaQ Stem Cells 2017;35:1065-1079.

Dataset Information

Mesenchymal Stem Cells in the Treatment of Traumatic Brain Injury.

Publications

Mesenchymal Stem Cells in the Treatment of Traumatic Brain Injury.

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