Enriching neural stem cell and pro-healing glial phenotypes with electrical stimulation after traumatic brain injury in male rats

Abstract

Traumatic Brain Injury (TBI) by an external physical impact results in compromised brain function via undesired neuronal death. Following the injury, resident and peripheral immune cells, astrocytes, and neural stem cells (NSCs) cooperatively contribute to the recovery of the neuronal function after TBI. However, excessive pro-inflammatory responses of immune cells, and the disappearance of endogenous NSCs at the injury site during the acute phase of TBI, can exacerbate TBI progression leading to incomplete healing. Therefore, positive outcomes may depend on early interventions to control the injury-associated cellular milieu in the early phase of injury. Here, we explore electrical stimulation (ES) of the injury site in a rodent model (male Sprague-Dawley rats) to investigate its overall effect on the constituent brain cell phenotype and composition during the acute phase of TBI. Our data showed that a brief ES for 1h on day 2 of TBI promoted pro-healing phenotypes of microglia as assessed by CD206 expression and increased the population of NSCs and Nestin+ astrocytes at 7 days post-TBI. Also, ES effectively increased the number of viable neurons when compared to the unstimulated control group. Given the salience of microglia and neural stem cells for healing after TBI, our results strongly support the potential benefit of the therapeutic use of ES during the acute phase of TBI to regulate neuroinflammation and to enhance neuroregeneration.Significance StatementTraumatic brain injury (TBI) occurs when a head injury leads to a disruption of normal function in the brain and is a major cause of death and disability, worldwide. The authors used electrical stimulation during the acute phase of TBI, which promoted pro-healing phenotypes of microglia and increased the number of neural stem cells and Nestin+ astrocytes, thereby enhancing neuronal viability. These findings support further study of electrical stimulation to regulate neuroinflammation and to enhance neuroregeneration after TBI.Graphical AbstractFIGURE 1.

Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair

“…Applied EFs are potent enough to efficiently divert NSCs from their default migratory pathways [ 264 ], supporting their utility in directing NSCs towards the lesion site to aid in neural repair. Proliferation kinetics and differentiation of NSC progeny is also impacted by applied EFs which have demonstrated pro-survival effects on NSCs and enhance differentiation of progeny into neurons and oligodendrocytes [ 258 ] Recent studies have discovered the potential of EF in ameliorating neuroinflammation by shifting microglial states from pro-inflammatory to the anti-inflammatory phenotype at lesion sites in the CNS in vivo [ 265 , 266 ]. Taken together, EFs have the potential to enhance directed migration and increase the survival of NSCs post-injury through both direct effects and niche-mediated alterations making EF application a feasible and customizable approach to improve functional recovery following SCI.…”