Combined fetal neural transplantation and nerve growth factor infusion: effects on neurological outcome following fluid-percussion brain injury in the rat

Abstract

<jats:p>This study was designed to evaluate the histological and behavioral impact of fetal neural transplantation with and without neurotrophin infusion in rats subjected to traumatic brain injury using a clinically relevant model of lateral fluid-percussion brain injury. Adult male Sprague-Dawley rats received lateral fluid-percussion brain injury of moderate severity (2.1-2.3 atm). Twenty-four hours after injury, minced fetal cortical grafts (E16) were stereotactically transplanted into the site of injury cavity formation (in 32 rats). Ten control animals received injections of saline. A third group of 29 animals that received transplants also underwent placement of a miniosmotic pump (immediately after transplantation) to continuously infuse nerve growth factor (NGF) directly into the region of graft placement for the duration of the experiment. A fourth group of eight animals underwent transplantation of fetal cortical cells that had been dissociated and placed in suspension. Animals were evaluated at 72 hours, 1 week, and 2 weeks after injury for cognitive function (using the Morris water maze), posttraumatic motor dysfunction, and transplant survival and morphology (using Nissl and modified Palmgren's silver staining techniques). Robust survival of whole-tissue transplants was seen in 65.6% of animals and was not increased in animals receiving NGF infusion. Animals receiving transplants of cell suspension had no surviving grafts. Brain-injured animals receiving transplants showed significant cognitive improvements compared with controls at the 2-week evaluation. Significantly improved memory scores were seen at all evaluation times in animals receiving both NGF and transplants compared with injured controls and compared with animals receiving transplants alone at the 72-hour and 1-week evaluations. Neurological motor function scores were significantly improved in animals receiving transplants alone and those receiving transplants with NGF infusion. Histological evaluation demonstrated differentiation of grafted cells, decreased glial scarring around transplants when compared with control animals, and the presence of neuronal fibers bridging the interface between graft and host. This study demonstrates that fetal cortical cells transplanted into the injured cortex of the adult rat can improve both posttraumatic cognitive and motor function and interact with the injured host brain.</jats:p>

Transplantation of Embryonic Neural Stem/Precursor Cells Overexpressing BM88/Cend1 Enhances the Generation of Neuronal Cells in the Injured Mouse Cortex

“…Additionally, a number of molecules have been used to enhance the capacity of embryonic stem cells and NPCs to repair CNS damage in animal models of traumatic brain injury. These include trophic factors such as NGF [48], GDNF [49], EGF [50], and FGF2 [7], cytokines such as erythropoietin [51], and also cell adhesion molecules [52–55] and extracellular matrix proteins including tenascin‐R [56]. In these paradigms, introduction of each individual factor resulted in improvement of either cell survival or migration or an increase in the differentiation potential of the transplanted cells towards a desirable pathway.…”

gThe Dorothy Russell Memorial Lecture* The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms

“…Further evidence for a functional role for neurotrophins in the sequelae of TBI can be obtained from studies administering these factors to brain‐injured animals. Intraparenchymal administration of NGF can attenuate cognitive but not neurobehavioural motor deficits or hippocampal cell loss following lateral FP brain injury [ 173, 174] and CCI brain injury in rats [ 40, 41]. Other studies have demonstrated that central NGF administration reduced the extent of apoptotic cell death in septal cholinergic neurons following experimental brain trauma [ 172] and reversed the trauma‐induced reductions in scopolamine‐evoked ACh release [ 40, 41].…”

Survival and integration of transplanted postmitotic human neurons following experimental brain injury in immunocompetent rats

“…Fetal tissue transplanted into the hostile microenvironment of the periinjured cortex after FPI to the brain in adult rats has demonstrated good graft survival, neurite outgrowth across the graft-host interface, attenuation of host neuronal cell death, and improvement in posttraumatic cognitive and motor function. 59,65,67 More specifically, at 4 weeks postinjury, fetal hippocampal grafts correlated with the preservation of ipsilateral hippocampal CA3 region pyramidal cells, and motor function was significantly improved at 2 weeks postinjury compared with injured control animals. 67 Injured rats that Object.…”

“…59 Despite the ability of fetal tissue to respond appropriately to, and functionally integrate into, the host parenchyma, the major inherent limitations of fetal CNS transplants include their cellular heterogeneity and relative unavailability as well as the potential ethical and practical issues associated with tissue procurement. 16,62,70 Many investigators have recently attempted to find an alternative source of neural progenitor cells or neuronal cells for transplantation that can be characterized, homogeneously expanded, and used for investigating the restorative neurobiological properties of both the surviving host neurons and the transplanted neuronal cells in the setting of brain injury.…”