title: Amelioration of Penetrating Ballistic-Like Brain Injury Induced Cognitive Deficits after Neuronal Differentiation of Transplanted Human Neural Stem Cells.
abstract: Penetrating traumatic brain injury (PTBI) is one of the major cause of death and disability worldwide. Previous studies with penetrating ballistic-like brain injury (PBBI), a PTBI rat model revealed widespread perilesional neurodegeneration, similar to that seen in humans following gunshot wound to the head, which is unmitigated by any available therapies to date. Therefore, we evaluated human neural stem cell (hNSC) engraftment to putatively exploit the potential of cell therapy that has been seen in other central nervous system injury models. Toward this objective, green fluorescent protein (GFP) labeled hNSC (400,000 per animal) were transplanted in immunosuppressed Sprague-Dawley (SD), Fisher, and athymic (ATN) PBBI rats 1 week after injury. Tacrolimus (3 mg/kg 2 days prior to transplantation, then 1 mg/kg/day), methylprednisolone (10 mg/kg on the day of transplant, 1 mg/kg/week thereafter), and mycophenolate mofetil (30 mg/kg/day) for 7 days following transplantation were used to confer immunosuppression. Engraftment in SD and ATN was comparable at 8 weeks post-transplantation. Evaluation of hNSC differentiation and distribution revealed increased neuronal differentiation of transplanted cells with time. At 16 weeks post-transplantation, neither cell proliferation nor glial lineage markers were detected. Transplanted cell morphology was similar to that of neighboring host neurons, and there was relatively little migration of cells from the peritransplant site. By 16 weeks, GFP-positive processes extended both rostrocaudally and bilaterally into parenchyma, spreading along host white matter tracts, traversing the internal capsule, and extending ∼13 mm caudally from transplantation site reaching into the brainstem. In a Morris water maze test at 8 weeks post-transplantation, animals with transplants had shorter latency to platform than vehicle-treated animals. However, weak injury-induced cognitive deficits in the control group at the delayed time point confounded benefits of durable engraftment and neuronal differentiation. Therefore, these results justify further studies to progress towards clinical translation of hNSC therapy for PTBI.
authors.affiliation: 1 Miami Project to Cure Paralysis , Miami, Florida.
authors.forename: Markus S
authors.initials: MS
authors.lastname: Spurlock
authors.affiliation: 1 Miami Project to Cure Paralysis , Miami, Florida.
authors.forename: Aminul I
authors.initials: AI
authors.lastname: Ahmed
authors.affiliation: 1 Miami Project to Cure Paralysis , Miami, Florida.
authors.forename: Karla N
authors.initials: KN
authors.lastname: Rivera
authors.affiliation: 1 Miami Project to Cure Paralysis , Miami, Florida.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yokobori
authors.affiliation: 1 Miami Project to Cure Paralysis , Miami, Florida.
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Lee
authors.affiliation: 1 Miami Project to Cure Paralysis , Miami, Florida.
authors.forename: Pingdewinde N
authors.initials: PN
authors.lastname: Sam
authors.affiliation: 2 Branch of Brain Trauma Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Shear
authors.affiliation: 3 Neuralstem, Inc. Germantown , Maryland.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hefferan
authors.affiliation: 3 Neuralstem, Inc. Germantown , Maryland.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hazel
authors.affiliation: 3 Neuralstem, Inc. Germantown , Maryland.
authors.forename: Karl K
authors.initials: KK
authors.lastname: Johe
authors.affiliation: 1 Miami Project to Cure Paralysis , Miami, Florida.
authors.forename: Shyam
authors.initials: S
authors.lastname: Gajavelli
authors.affiliation: 2 Branch of Brain Trauma Neuroprotection and Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tortella
authors.affiliation: 1 Miami Project to Cure Paralysis , Miami, Florida.
authors.forename: Ross M
authors.initials: RM
authors.lastname: Bullock
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000175:diagnosis / Q000628:therapy; D002454:Cell Differentiation / Q000502:physiology*; D003072:Cognition Disorders / Q000175:diagnosis / Q000628:therapy*; D020197:Head Injuries, Penetrating / Q000175:diagnosis / Q000628:therapy*; D006801:Humans; D058953:Neural Stem Cells / Q000637:transplantation*; D009474:Neurons / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation / Q000379:methods*
keywords: PBBI; TBI; behavior deficit; cell transplantation; hNSC; neuronal differentiation