Introduction: Progressive tissue loss drives disability in severe PTBI survivors. No current treatments mitigate secondary damage. Recently our lab elucidated role of TBI induced neuroinflammation in driving tissue loss and robust durable neural stem cell (NSC) engraftment. We hypothesized that clinical trial grade human NSC (hNCS) transplant location would influence the progression of secondary damage.

Methods: To test the hypothesis, a group of 40 rats was randomized to following groups: (Gr1) PTBI+vehicle, (Gr2) no injury + hNCS, (Gr3) PTBI+hNSCs in lesion penumbra or (Gr4) PTBI+hNSCs intralesion. All injured rats had unilateral PTBI and all transplants were done 1-week post injury with a million cells and subsequent immunosuppression. 12 weeks post-transplant (measure of robust durable engraftment) brain sections were stained to assess (1) lesion volume/spared tissue (progression/neuroprotection), (2) motor ability using grid walk, (3) immunohistochemsitry.

Results: Statistical analysis showed significant reduction of mean lesion volume, increased motor cortex sparing (P<0.0001 Gr3 vs Gr1) but not Gr4 vs Gr1. hNSC engraftment was significantly greater in Gr3, 4 vs Gr2. Transplant survival or neuronal differentiation did not differ between Gr3 and 4. On grid walk Gr 3 and 4 animals had significantly fewer foot faults compared to Gr1, albeit not enough to abolish injury effect (vs Gr2).

Conclusions: At 12 weeks post-transplantation (1) hNSC mediated neuroprotective effect is location dependent whereas engraftment and differentiation weren’t. (2) Motor recovery was due to neuroprotection rather than cell replacement. In aggregate with ongoing safety study data, our results suggest that neural stem cells offer an opportunity to mitigate TBI induced disability and warrants further investigation as part of a clinical trial.

Patient Care: TBI is a critical public health problem and one of the leading causes of death and disability around the globe. The World Health Organization (WHO) and the World Bank (WB) estimate that 69 million (95% CI 64-74 million) individuals suffer from TBI every year, with Southeast Asian and Western Pacific regions experiencing the greatest overall burden. While road traffic accidents are still the primary cause of TBI worldwide, firearm injury has become an increasingly serious problem in the US. TBI affects 1.7 million people in the US and kills 50,000 people every year. Timely and aggressive management of acute trauma patients has lowered the fatality rate but does not eliminate the socioeconomic consequences of TBI. In a survey of service members, of which 69% had severe TBI, only 21% could return to work at 1-year post injury. Clearly TBI poses a significant burden for patients and the healthcare system at large, even under current best practice guidelines. The underlying pathophysiology indicates that loss of cells combined with incomplete endogenous repair mechanisms may be a cause of disability. Most of the disability arises from secondary injury days and months after primary. Currently no treatment strategies exist to mitigate this continued secondary damage. This is where cell replacement via neural stem cell transplantation is a putative therapeutic approach based upon preclinical studies. My lab has already shown robust durable engraftment, lesion volume reduction and preliminary motor functionality improvement in PTBI rat model (PBBI). Ongoing analysis of 6 month safety in PTBI athymic rats also shows no transplant derived tumors or participation of transplanted cells in rats own tumors. In aggregate, our research holds promise for mitigating the progressive, irreversible quality-of-life degradation that patients with severe TBI experience and thus curtails the overall societal burden of TBI.

Learning Objectives: By the conclusion of this session, participants should be able to 1) Describe the effect of transplant location on Human neural stem cells mediated mitigation of penetrating TBI induced progressive tissue loss, 2) Consider alternative uses of neural stem cell transplants 3) Understand the potential for hNSC in prevention of loss / regaining of motor ability.

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