Endogenous Repair Signaling after Brain Injury and Complementary Bioengineering Approaches to Enhance Neural Regeneration

Abstract

Traumatic brain injury (TBI) affects 5.3 million Americans annually. Despite the many long-term deficits associated with TBI, there currently are no clinically available therapies that directly address the underlying pathologies contributing to these deficits. Preclinical studies have investigated various therapeutic approaches for TBI: two such approaches are stem cell transplantation and delivery of bioactive factors to mitigate the biochemical insult affiliated with TBI. However, success with either of these approaches has been limited largely due to the complexity of the injury microenvironment. As such, this review outlines the many factors of the injury microenvironment that mediate endogenous neural regeneration after TBI and the corresponding bioengineering approaches that harness these inherent signaling mechanisms to further amplify regenerative efforts.

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

“…The neurotrophic role of EGFR signaling may promote recovery after injury to the CNS through increased NSC/NPC proliferation and differentiation in the VSZ niches and migration toward the injured area to replenish the injured neurons and facilitation of axon regeneration (6,217,599). HB-EGF, EGF, and EGFR expression increase in the SVZ and the areas surrounding the injury (11,43,258,390,450), and EGF or TGF-␣ infusion can promote axon regeneration (217, 599), while specific forebrain HB-EGF deletion exacerbates brain injury (407).…”

Where do you come from and what are you going to become, reactive astrocyte?

“…Under physiological conditions in vivo they predominantly give rise to neuroblasts, which migrate to the olfactory bulb and generate new neurons (5). However, traumatic and ischemic events profoundly affect the fate of these cells, not only by dramatically modifying their environment, but also by recruiting them outside their "natural" migratory pathway towards the injury site, in an often-unsuccessful attempt of regeneration (6). In fact, newborn neuroblasts do not functionally integrate in the damaged tissue, and undergo cell death very quickly.…”

Treating childhood traumatic brain injury with autologous stem cell therapy

“…Unfortunately, there is little information to corroborate the efficacy of stem cell treatment six weeks or longer after neonatal TBI although stem cell transplants have been demonstrated to be effective in chronic stage in other diseases, such as stroke, HIE, and adult TBI. The ability of stem cells like BMSCs to deliver trophic factors may represent an alternative option for treating chronic diseases [61–62]. Because trophic factors are known to help neurons function, stem cells’ ability to deliver them may help restore the injured brain long after the initial injury, in conjunction with stem cell-paved biobridges [62–64] and the elusive cell replacement-based regenerative medicine [28, 62–64].…”

“…The ability of stem cells like BMSCs to deliver trophic factors may represent an alternative option for treating chronic diseases [61–62]. Because trophic factors are known to help neurons function, stem cells’ ability to deliver them may help restore the injured brain long after the initial injury, in conjunction with stem cell-paved biobridges [62–64] and the elusive cell replacement-based regenerative medicine [28, 62–64]. Though the mechanism of action of stem cells is not clearly known, recent studies have posed the possibility of them working through a biobridge: a pathway that allows host neurogenic cells to travel to the site of injury and initiate endogenous repair mechanisms [63].…”