Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI

Abstract

Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including “The Lancet Neurology Commission” and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection.

Commonly Overlooked Factors in Biocompatibility Studies of Neural Implants

“…[15,16,55] Clinical applications can be segregated between patients with healthy brain tissues but loss of functionality through localized denervation due to injury or disease, [35,56,57] or extensively diseased brain tissues (Parkinson's, Alzheimer's, multiple sclerosis, etc.). [58][59][60] Limited efficacy of a device to provide adequate therapeutic benefit may not be entirely due to device fault or anomalous tissue healing; overall advanced degenerated state of the tissue, incomplete or poor targeting/stimulation of affected areas, progressive loss of signal as disease state advances, or combinations thereof may dominate. [61]…”

“…[192] In line with this suggestion, incomplete inflammatory action has been suspected as a possible cause of failure of clinical trials investigating pharmaceutical agents that downregulate microglial activity following stroke and TBI. [60,194]…”

How neural stem cells promote the repair of brain injury through immunoregulation

“…[ 11 ] Besides, NSC transplants could confer neuroprotection to alleviate tissue loss via inhibiting microglial pyroptosis and promoting phagocytosis by surviving activated microglia, which may be related to the decreased NLRP3 activation. [ 12 ]…”

Injury-Transplantation Interval-Dependent Amelioration of Axonal Degeneration and Motor Deficit in Rats with Penetrating Traumatic Brain Injury

“…Previous failures of neuroprotective trials 3 , 20–24 have led to alternative approaches, including recruitment of endogenous neural stem cells (NSCs) or replacement by transplantation exogenous NSCs to rebuild circuitry. 25 , 26 Both pre-clinical and clinical attempts to increase endogenous NSCs have failed to repair injured brains. 27 , 28 On the other hand, transplantation of exogenous human NSCs (hNSCs) in amyotrophic lateral sclerosis, 29–31 stroke, 32 spinal cord injury, 33 , 34 and recently in multiple sclerosis patients 35 have been shown to be stable and safe.…”