RESUMO
Traumatic brain injury (TBI) is a cause of disability and death worldwide, but there are currently no specific treatments for this condition. Release of excess reactive oxygen species (ROS) in the injured brain leads to a series of pathological changes; thus, eliminating ROS could be a potential therapeutic strategy. Herein, we synthesized insulin-incubated ultrasmall palladium (Pd@insulin) clusters via green biomimetic chemistry. The Pd@insulin clusters, which were 3.2 nm in diameter, exhibited marked multiple ROS-scavenging ability testified by the theoretical calculation. Pd@insulin could be rapidly excreted via kidney-urine metabolism and induce negligible adverse effects after a long-time treatment in vivo. In a TBI mouse model, intravenously injected Pd@insulin clusters aggregated in the injured cortex, effectively suppressed excessive ROS production, and significantly rescued motor function, cognition and spatial memory. We found that the positive therapeutic effects of the Pd@insulin clusters were mainly attributed to their ROS-scavenging ability, as they inhibited excessive neuroinflammation, reduced cell apoptosis, and prevented neuronal loss. Therefore, the ability of Pd@insulin clusters to effectively eliminate ROS, as well as their simple structure, easy synthesis, low toxicity, and rapid metabolism may facilitate their clinical translation for TBI treatment.
Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Insulina , Camundongos , Paládio/farmacologia , Paládio/uso terapêutico , Espécies Reativas de Oxigênio/metabolismoRESUMO
Traumatic brain injury poses serious physical, psychosocial, and economic threats. Although systemic administration of stem cell-derived exosomes has recently been proven to be a promising modality for traumatic brain injury treatment, they come with distinct drawbacks. Luckily, various biomaterials have been developed to assist local delivery of exosomes to improve the targeting of organs, minimize nonspecific accumulation in vital organs, and ensure the protection and release of exosomes. In this study, we developed an electrospun nanofibrous scaffold to provide sustained delivery of dual exosomes derived from mesenchymal stem cells and neural stem cells for traumatic brain injury treatment. The electrospun nanofibrous scaffold employed a functionalized layer of polydopamine on electrospun poly(ε-caprolactone) nanofibers, thereby enhancing the efficient incorporation of exosomes through a synergistic interplay of adhesive forces, hydrogen bonding, and electrostatic interactions. First, the mesenchymal stem cell-derived exosomes and the neural stem cell-derived exosomes were found to modulate microglial polarization toward M2 phenotype, play an important role in the modulation of inflammatory responses, and augment axonal outgrowth and neural repair in PC12 cells. Second, the nanofibrous scaffold loaded with dual stem cell-derived exosomes (Duo-Exo@NF) accelerated functional recovery in a murine traumatic brain injury model, as it mitigated the presence of reactive astrocytes and microglia while elevating the levels of growth associated protein-43 and doublecortin. Additionally, multiomics analysis provided mechanistic insights into how dual stem cell-derived exosomes exerted its therapeutic effects. These findings collectively suggest that our novel Duo-Exo@NF system could function as an effective treatment modality for traumatic brain injury using sustained local delivery of dual exosomes from stem cells.
Assuntos
Lesões Encefálicas Traumáticas , Exossomos , Células-Tronco Mesenquimais , Nanofibras , Células-Tronco Neurais , Exossomos/metabolismo , Exossomos/química , Animais , Lesões Encefálicas Traumáticas/terapia , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Nanofibras/química , Ratos , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/citologia , Células PC12 , Camundongos , Alicerces Teciduais/química , Poliésteres/química , Proteína Duplacortina , Polímeros/química , Masculino , Indóis/químicaRESUMO
Microglia are brain resident cells that function as brain phagocytic macrophages. The inflammatory responses of microglia induced by pathologic insults are key regulators in the progression of various neurological disorders. Currently, little is known about how these responses are regulated intrinsically. Here, it is observed that LPS-activated microglia exhibit distinct N6-methyladenosine (m6A) methylation patterns that are positively correlated with the expression patterns of corresponding mRNAs. High-throughput analyses and molecular studies both identified Igf2bp1 as the most significantly regulated m6A modifiers in activated microglia. Perturbation of function approaches further indicated Igf2bp1 as a key mediator for LPS-induced m6A modification and microglial activation presumably via enhancing the m6A methylation and stability of Gbp11 and Cp mRNAs. Thus, our study provides a possible mechanism for the m6A methylation-mediated microglia regulation and identifies Igf2bp1 as a potential target for modulating the inflammatory responses of microglia.