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Potential of mesenchymal stem cells alone, or in combination, to treat traumatic brain injury.

ABSTRACT: Traumatic brain injury (TBI) causes death and disability in the United States and around the world. The traumatic insult causes the mechanical injury of the brain and primary cellular death. While a comprehensive pathological mechanism of TBI is still lacking, the focus of the TBI research is concentrated on understanding the pathophysiology and developing suitable therapeutic approaches. Given the complexities in pathophysiology involving interconnected immunologic, inflammatory, and neurological cascades occurring after TBI, the therapies directed to a single mechanism fail in the clinical trials. This has led to the development of the paradigm of a combination therapeutic approach against TBI. While there are no drugs available for the treatment of TBI, stem cell therapy has shown promising results in preclinical studies. But, the success of the therapy depends on the survival of the stem cells, which are limited by several factors including route of administration, health of the administered cells, and inflammatory microenvironment of the injured brain. Reducing the inflammation prior to cell administration may provide a better outcome of cell therapy following TBI. This review is focused on different therapeutic approaches of TBI and the present status of the clinical trials.

SUBMITTER: Willing AE

PROVIDER: S-EPMC7248546 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Potential of mesenchymal stem cells alone, or in combination, to treat traumatic brain injury.

Willing Alison E AE Das Mahasweta M Howell Mark M Mohapatra Shyam S SS Mohapatra Subhra S

CNS neuroscience & therapeutics 20200310 6

Traumatic brain injury (TBI) causes death and disability in the United States and around the world. The traumatic insult causes the mechanical injury of the brain and primary cellular death. While a comprehensive pathological mechanism of TBI is still lacking, the focus of the TBI research is concentrated on understanding the pathophysiology and developing suitable therapeutic approaches. Given the complexities in pathophysiology involving interconnected immunologic, inflammatory, and neurologic ...[more]

PMID: 32157822

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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: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:Corneal injury (CI) affects corneal integrity and transparency, deteriorating the patient's quality of life. This study aimed to explore the molecular mechanisms by which exosomes secreted from human umbilical cord mesenchymal stem cells (hucMSC-Exos) affect autophagy in human corneal epithelial cells (HCECs) and CI models. We isolated and identified hucMSC-Exos using nanoparticle tracking analysis, transmission electron microscopy, and western blotting. The effects of hucMSC-Exos combined with autophagy regulators on HCECs and CI mice were assessed using cell viability assays, scratch assay, cell cycle assay, apoptosis assay, corneal fluorescein staining, haze grades, pathological examinations, western blotting, and quantitative polymerase chain reaction (qPCR). In vitro results indicated that hucMSC-Exos combined with the autophagy activator had positive effects in promoting the cell proliferation, migration capacity, and the cell cycle by upregulating the proportions of cells in the S phase and the expression of PCNA, Cyclin A, Cyclin E, and CDK2. Meanwhile, the combination treatment reduced the apoptotic rate of HCECs. In vivo results indicated that hucMSC-Exos especially combined them with the autophagy activator significantly alleviated corneal epithelial defects and stromal opacity, reduced the levels of the apoptotic markers Bax and cleaved Caspase-3, reduced the inflammatory response products TNF-α, IL-1β, IL-6, and CXCL-2, and increased the Bcl-2. This was achieved by upregulating pAMPK/AMPK and pULK1/ULK1 ratios, and Beclin-1 and LC3B II/I, and by downregulating the pmTOR/mTOR ratio and p62. In contrast, clinical indications, apoptosis, and inflammation were aggravated after the application of the autophagy inhibitor. HucMSC-Exos combined with an autophagy activator significantly enhanced HCECs functions and alleviated corneal defects, apoptosis, and inflammation by activating the autophagy signaling pathway, AMPK-mTOR-ULK1, providing a new biological therapy for corneal wound healing and ocular surface regeneration.

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Potential of mesenchymal stem cells alone, or in combination, to treat traumatic brain injury.

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Potential of mesenchymal stem cells alone, or in combination, to treat traumatic brain injury.

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