Engineering Glial Scar for Brain Tissue Regeneration After Traumatic Injury
Abstract
Traumatic brain injury (TBI) occurs when a sudden trauma or head injury disrupts the function of the brain, which may result from explosive devices, heavy weaponry, falls, and vehicle or motorcycle accidents. Specifically, TBI has been called the signature wound of the Iraq and Afghanistan wars. The number of Veterans with TBI has risen sharply in recent years. Current TBI treatments have been focused on medications and rehabilitation therapies, such as physical therapy, occupational therapy, and speech-language therapy. However, current treatments are not proven to restore lost neurological function and deficits after TBI. A successful TBI therapy requires repopulation of the lesion site with functional neurons and vascular structures for deficit repair. Reactive gliosis and scarring are frequently described after TBI. Gliosis occurs when glial cells form a compact border around an area of tissue damage. Currently viral vector-mediated transduction of transcription factors could directly or indirectly convert glial cells into neurons in the adult brain. This would prevent gliosis and scarring and constitute a novel therapeutic strategy for neural regeneration. However, clinical application of this strategy is limited by several issues: safe and efficient gene delivery methods, long-term survival of induced neurons, sufficient induced neurons needed for the lesion repair, appropriate maturation and integration of induced neurons with the host circuitry for beneficial functions. To address these issues, the goal of this proposal is to develop a combinational approach to engineer activated glial cells for neural regeneration after TBI. We will establish an effective nanoparticle-mediated transfection method to reprogram astrocytes into neuroblasts using a unique non-viral transfection method for gene delivery. Second, to improve the survival of these converted cells, especially at the TBI lesion site, reconstructing the damaged vasculature network is crucial. We have developed a structurally optimized hydrogel that generates a robust neovascular network at the lesion site. Third, various trophic factors, including brain-derived neurotrophic factor, facilitate neuronal differentiation and maturation. Based on the angiogenic hydrogel, we will develop a novel fiber-hydrogel composite for sustained release of these growth factors to support neuronal differentiation of converted neuroblasts in vitro. Finally, we will evaluate the tissue regeneration capability of optimized nanoparticles and tailored composites at the TBI lesion site. Our central hypothesis is that reactive astrocytes, when provided with guidance for in situ conversion, migration, and differentiation, will develop into functional neurons supporting brain tissue regeneration after traumatic injury. The important concept of in situ direct converting astrocytes to neuroblasts by nanoparticles and controlling neural regeneration of these converted neuroblasts by composites will establish a framework in treating central nervous system (CNS) injuries and diseases. Compared to exogenous stem cells, in situ direct manipulation of endogenous glial cells is easier, safer, and more efficient. This approach avoids in vitro cell handling associated with exogenous stem cells and potential xeno-contamination and immune-compatibility issues. This study will provide an important advance over current treatments for CNS tissue regeneration. In particular, our unique approach meets the intent of the Traumatic Brain Injury and Psychological Health Research Program Idea Development Award, in particular, for the sub-area of interventions to promote sustained functional recovery on sensory and locomotor dysfunction after brain injury and address cognitive functioning and reserve. Our approach can ultimately treat TBI patients with sustainable structural repair and functional recovery, which directly benefit wounded Service Members, Veterans, and beneficiaries, and the American pu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210785
Entities
People
- Xiaowei Li
Organizations
- United States Army
- Washington University in St. Louis