Abstract
Background: Numerous studies have reported a beneficial impact of neural progenitor cell transplantation on functional outcome after traumatic brain injury (TBI) during short and medium follow-up periods. However, our knowledge regarding long-term functional effects is fragmentary while a direct comparison between local and systemic transplantation is missing so far.Objectives: This study investigated the long-term (12 week) impact of human fetal neuronal progenitor cell (hNPC) transplantation 24 h after severe TBI in rats.Methods: Cells were either transplanted stereotactically (1 × 105) into the putamen or systemically (5 × 105) via the tail vein. Control animals received intravenous transplantation of vehicle solution.Results: An overall functional benefit was observed after systemic, but not local hNPC transplantation by area under the curve analysis (p < 0.01). Surprisingly, this effect vanished during later stages after TBI with all groups exhibiting comparable functional outcomes 84 days after TBI. Investigation of cell-mediated inflammatory processes revealed increasing microglial activation and macrophage presence during these stages, which was statistically significant after systemic cell administration (p < 0.05). Intracerebral hNPC transplantation slightly diminished astrogliosis in perilesional areas (p < 0.01), but did not translate into a permanent functional benefit. No significant effects on angiogenesis were observed among the groups.Conclusion: Our results suggest the careful long-term assessment of cell therapies for TBI, as well as to identify potential long-term detrimental effects of such therapies before moving on to clinical trials. Moreover, immunosuppressive protocols, though widely used, should be rigorously assessed for their applicability in the respective setup.
Highlights
Acute traumatic brain injury (TBI) is followed by a complex cascade of pathophysiological sequelae such as excitotoxicity, formation of free radicals, release of inflammatory molecules, as well as diffuse axonal and neuronal injury
An overall functional benefit was observed after systemic, but not local human fetal neuronal progenitor cell (hNPC) transplantation by area under the curve analysis (p < 0.01). This effect vanished during later stages after TBI with all groups exhibiting comparable functional outcomes 84 days after TBI
Functional outcome There were no statistically significant differences in performance for both behavioral tests among groups in the rotarod and modified neurological severity score (mNSS) tests before TBI (d-1, p > 0.4, data not shown)
Summary
Acute traumatic brain injury (TBI) is followed by a complex cascade of pathophysiological sequelae such as excitotoxicity, formation of free radicals, release of inflammatory molecules, as well as diffuse axonal and neuronal injury. These processes exacerbate blood–brain barrier (BBB) breakdown, activate micro-(Napoli and Neumann, 2009) and astroglia (Silver and Miller, 2004) and enhance leukocyte migration to the lesion site, cumulating into subacute (“secondary”) brain damage (McIntosh et al, 1996; Teasdale and Graham, 1998) with a net loss of cerebral tissue and function. Our knowledge regarding long-term functional effects is fragmentary while a direct comparison between local and systemic transplantation is missing so far
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