Human neural stem cell transplant location–dependent neuroprotection and motor deficit amelioration in rats with penetrating traumatic brain injury

Abstract

BACKGROUND Penetrating traumatic brain injury induces chronic inflammation that drives persistent tissue loss long after injury. Absence of endogenous reparative neurogenesis and effective neuroprotective therapies render injury-induced disability an unmet need. Cell replacement via neural stem cell transplantation could potentially rebuild the tissue and alleviate penetrating traumatic brain injury disability. The optimal transplant location remains to be determined. METHODS To test if subacute human neural stem cell (hNSC) transplant location influences engraftment, lesion expansion, and motor deficits, rats (n = 10/group) were randomized to the following four groups (uninjured and three injured): group 1 (Gr1), uninjured with cell transplants (sham+hNSCs), 1-week postunilateral penetrating traumatic brain injury, after establishing motor deficit; group 2 (Gr2), treated with vehicle (media, no cells); group 3 (Gr3), hNSCs transplanted into lesion core (intra); and group 4 (Gr4), hNSCs transplanted into tissue surrounding the lesion (peri). All animals were immunosuppressed for 12 weeks and euthanized following motor assessment. RESULTS In Gr2, penetrating traumatic brain injury effect manifests as porencephalic cyst, 22.53 ± 2.87 (% of intact hemisphere), with p value of <0.0001 compared with uninjured Gr1. Group 3 lesion volume at 17.44 ± 2.11 did not differ significantly from Gr2 (p = 0.36), while Gr4 value, 9.17 ± 1.53, differed significantly (p = 0.0001). Engraftment and neuronal differentiation were significantly lower in the uninjured Gr1 (p < 0.05), compared with injured groups. However, there were no differences between Gr3 and Gr4. Significant increase in cortical tissue sparing (p = 0.03), including motor cortex (p = 0.005) was observed in Gr4 but not Gr3. Presence of transplant within lesion or in penumbra attenuated motor deficit development (p < 0.05) compared with Gr2. CONCLUSION In aggregate, injury milieu supports transplanted cell proliferation and differentiation independent of location. Unexpectedly, cortical sparing is transplant location dependent. Thus, apart from cell replacement and transplant mediated deficit amelioration, transplant location–dependent neuroprotection may be key to delaying onset or preventing development of injury-induced disability. LEVEL OF EVIDENCE Preclinical study evaluation of therapeutic intervention, level VI.

Recent advances in the treatment of traumatic brain injury with autologous and non-autologous multipotent stem and progenitor cells: preclinical models and clinical trials

“…They transplanted hNSCs into the core or around the lesion one week after the injury. After 12 weeks, neuronal differentiation and motor function improvement were observed in both groups but sparing of a larger volume of intact brain including cortex makes the peri-lesion administration a preferable choice [40]. Beretta et al made an attempt to see the effects of hNSCs on posttraumatic hyperexcitable brain.…”

Brain Extract of Subacute Traumatic Brain Injury Promotes the Neuronal Differentiation of Human Neural Stem Cells via Autophagy

“…Endogenous neurogenesis is limited due to the challenging environment after TBI [ 28 , 29 ]. Recently, NSCs have been successfully transplanted into TBI model rodents and shown to result in a significant improvement in neurological function [ 10 , 11 , 12 ]; however, clinical translation is still lacking. With TBI as a major cause of emergencies, different phases of TBI are drastically varying microenvironments to grafted NSCs.…”

“…Thus, reconstructing the injured neuron circuit through grafting neural stem cells (NSCs) has been considered aa a promising cell therapy for TBI [ 8 , 9 ]. In a rodent TBI model, NSC transplantation has shown an improvement of cognitive and motor functions [ 10 , 11 , 12 ]. Recent studies also applied various growth factors, e.g., BDNF, GDNF, and bFGF, to promote the viability of grafted NSCs under TBI conditions [ 13 , 14 , 15 ].…”

Stem Cell Therapies for Central Nervous System Trauma: The 4 Ws—What, When, Where, and Why

“…There is a cascade of biochemical and cellular processes in the acute-subacute stages that can be affected by transplanted NPCs with reduced degeneration as a result. Several transplantation studies of murine 40 and human 41 , 42 NPCs have shown improved functional recovery that can be attributed to neuroprotection, that is, reduced degeneration of compromised host neurons. Neuroprotection is a key mechanism by which fNPCs can improve functional outcomes after experimental SCI, and human fNPCs derived from the spinal cord are more effective than fNPCs from the forebrain.…”