One step at a time, stem cell therapy for traumatic brain injury needs two more breakthroughs

Firearm injury is a serious public health problem in the United States (US) costing more than $70-75 billion annually [1,2]. Nonfatal gunshot injuries in the US have increased from 20.5 per 100,000 Americans in 2002 to 23.7 per 100,000 by 2011, mainly due to increased assaults [3]. Despite increasing incidence, timely neurosurgical intervention aided with improved neuro imaging and advances in acute trauma management have lowered the firearm fatality rate [4-6]. Thus, among the estimated 5.3 million people living in the US with traumatic brain injury (TBI)-related disability, the proportion of gun-shot wound survivors has been rising steadily [3,7-11]. Among head injuries, penetrating injuries (PTBI) are associated with the worst outcomes [12,13], and no effective restorative treatment beyond physical therapy is currently available to mitigate post-TBI disability [12-14]. Therefore, there is an urgent need to explore additional treatment options to address long term TBI related disabilities. Studies with preclinical models have demonstrated that failure of injuryinduced regenerative neurogenesis; chronic inflammation and atrophy underlie poor outcomes [15-17]. Loss of neurons and consequent brain atrophy is a consistent neuro pathological finding in TBI survivors and may underlie long-term functional deficits, resulting in reduced executive and integrative capability [18-20]. Human PTBI neuro pathological findings support neuronal and axonal loss with significant brain atrophy [21]. The milestones in neural stem cell (NSC) research were outlined in a review by Gage and Temple, pioneers of the field [22]. NSCs afford the plasticity to generate, repair, and change nervous system function thus are of great interest to basic scientists as well as clinicians. NSCs have not blossomed into a therapeutic as yet and in this article some the issues that underlies the dormancy are discussed. The cell therapy field needed to address four main issues before clinical trials can be started. Firstly, production of the cell therapy candidate under good manufacturing conditions (GMP), second discovery of efficient immunosuppression, third demonstration of therapeutic benefit under controlled conditions. Three decades of basic science has managed to address first two issues.