Cell Type-Associated Differences in Migration, Survival, and Immunogenicity following Grafting in CNS Tissue (original) (raw)
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Neurosurgery, 2005
We have previously shown that constitutively active epidermal growth factor receptor signaling enhances the survival and motility of engrafted neural stem cells (NSCs) when transplanted into normal adult brain. In the present study, using the C17.2 NSC line stably transfected with the constitutively active epidermal growth factor receptor vIII, we sought to evaluate the phenotype of NSCs after engraftment into the milieu of traumatic head injury. METHODS: We performed intracerebral NSC transplantation with C17.2 NSCs overexpressing the active epidermal growth factor receptor vIII receptor into the ipsilateral (n ϭ 17) or contralateral (n ϭ 19) corpus callosum at 48 hours after severe experimental traumatic brain injury (TBI) or after sham injury (n ϭ 12) in rats. RESULTS: All sham-injured animals (100%) showed NSC graft survival, compared with 65% of brain-injured animals receiving ipsilateral NSC transplants, and only 10% of brain-injured animals had surviving transplants after engraftment into the contralateral uninjured corpus callosum. A marked elevation of nerve growth factor (pg/mg protein) was observed at 72 hours after injury in the injured hemisphere (x ϭ 80 Ϯ 10 pg/mg) compared with the contralateral uninjured hemisphere (35 Ϯ 0 pg/mg) (P Ͻ 0.05), and this elevation of nerve growth factor may have contributed to enhanced survival of engrafted NSCs. In uninjured control animals, NSC transplants proliferated actively, as evidenced by incorporation of bromodeoxyuridine. After TBI, however, transplanted NSCs failed to proliferate, regardless of the site of implantation. Morphologically, NSCs transplanted into the injured brain showed extensive process formation suggestive of a more differentiated phenotype, in contrast to NSCs engrafted into uninjured brain that appear undifferentiated, with round soma and no processes. NSCs transplanted into the corpus callosum of brain-injured animals also expressed NG2, a pro-oligodendrocyte marker that was not seen in cells transplanted into uninjured brain. Although migration of NSCs was much more pronounced in the uninjured brain, 2 weeks after TBI, NSCs transplanted into the ipsilateral corpus callosum were found to have migrated to the injury cavity. Moreover, NSCs transplanted into the corpus callosum contralateral to the site of injury were observed crossing the corpus callosum by 2 weeks after transplantation. CONCLUSION: Our results suggest that the environment associated with acute experimental TBI can significantly modulate the phenotype and migratory patterns of the engrafted NSC. These findings have particularly important implications for transplantation of NSCs into the traumatically injured nervous system.
Inflammation and Stem Cell Migration to the Injured Brain in Higher Organisms
Stem Cells and Development, 2009
Current treatments of neurological disorders such as Parkinson's disease and stroke are only partially effective. Consequently new therapies such as cell transplantation are of great interest. Cell therapy has shown promising results in animal models and in limited clinical trials. This form of treatment does have its own concerns, such as what factors control the survival and/or migration of the transplanted cells and how do they exert their benefi t. Recent studies on tracking the transplants, such as prelabeling of the cells prior to transplant, and those elucidating the role of chemokines, as well as microglial and infl ammatory responses, that may initiate the movement and survival of these cells are discussed in this review. A better understanding of these mechanism-driven pathways of neural repair will facilitate the clinical application of cell therapy for neurological disorders.
Cell transplantation, 2016
Neural stem cells (NSCs) promote recovery from brain trauma, but neuronal replacement is unlikely the sole underlying mechanism. We hypothesize that grafted NSCs enhance neural repair at least partially through modulating the host immune response after traumatic brain injury (TBI). C57BL/6 mice were intracerebrally injected with primed human NSCs (hNSCs) or vehicle 24 hours after a severe controlled cortical impact injury. Six days after transplantation, brain tissues were collected for Western blot and immunohistochemical analyses. Observations included indicators of microglia/macrophage activation, M1 and M2 phenotypes, axonal injury detected by amyloid precursor protein (APP), lesion size, and the fate of grafted hNSCs. Animals receiving hNSC transplantation did not show significant decreases of brain lesion volumes compared to transplantation procedures with vehicle alone, but did show significantly reduced injury-dependent accumulation of APP. Furthermore, intracerebral transpl...
Experimental Neurology, 2006
Neural stem cells have emerged as a promising therapeutic tool in CNS disease and injuries. In the clinical setting, cultured human neural stem/ progenitor cells (hNSC) are an attractive possibility for transplantation to the damaged brain. However, transplantation of hNSC requires toxic immunosuppressive treatment to avoid rejection. The aim of the current study was to evaluate if shortening the duration of immunosuppression by cyclosporin A would affect hNSC survival and differentiation after transplantation to the site of a focal brain injury in the rat. hNSC were xenografted to the hippocampus and the medial limit of an experimentally induced cortical contusion. The animals received immunosuppression for either 6 or 3 weeks or no immunosuppression. The status of the grafted human cells was analysed by immunohistochemistry. No statistically significant differences were observed between the two immunosuppressed groups regarding graft survival, migration or proliferation at 6 weeks post-transplantation. In contrast, the graft survival was extremely poor in the non-immunosuppressed group. Furthermore, the expression of the differentiation markers nestin, neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) in the transplanted cells did not differ significantly between the two immunosuppressed groups. Moreover, a fourth group of eight animals that were immunosuppressed for 3 weeks were allowed to survive for 6 months. Five of these rats demonstrated robust graft survival in the hippocampus and scattered cells in the cortex. This study demonstrates the importance of immunosuppression but also the possibility of shortening immunosuppression without impacting on the phenotype of the grafted hNSC.
Frontiers in neurology, 2015
Brain injury is a major cause of long-term disability. The possibility exists for exogenously derived neural progenitor cells to repair damage resulting from brain injury, although more information is needed to successfully implement this promising therapy. To test the ability of neural progenitor cells (NPCs) obtained from rats to repair damaged neocortex, we transplanted neural progenitor cell suspensions into normal and injured slice cultures of the neocortex acquired from rats on postnatal day 0-3. Donor cells from E16 embryos were obtained from either the neocortex, including the ventricular zone (VZ) for excitatory cells, ganglionic eminence (GE) for inhibitory cells or a mixed population of the two. Cells were injected into the ventricular/subventricular zone (VZ/SVZ) or directly into the wounded region. Transplanted cells migrated throughout the cortical plate with GE and mixed population donor cells predominately targeting the upper cortical layers, while neocortically deri...
Immunobiology, 2013
Although cell transplantation is increasingly suggested to be beneficial for the treatment of various neurodegenerative diseases, the therapeutic application of such intervention is currently hindered by the limited knowledge regarding central nervous system (CNS) transplantation immunology. In this study, we aimed to investigate the early post transplantation innate immune events following grafting of autologous mesenchymal stromal cells (MSC) in the CNS of immune competent mice. First, the survival of grafted Luciferase/eGFP-expressing MSC (MSC-Luc/eGFP) was demonstrated to be stable from on day 3 post implantation using in vivo bioluminescence imaging (BLI), which was further confirmed by quantitative histological analysis of MSC-Luc/eGFP graft survival. Additional histological analyses at week 1 and week 2 post grafting revealed the appearance of (i) graft-surrounding/-invading Iba1+ microglia and (ii) graft-surrounding GFAP+ astrocytes, as compared to day 0 post grafting. While the density of graft-surrounding astrocytes and microglia did not change between week 1 and week 2 post grafting, the density of graft-invading microglia significantly decreased between week 1 and week 2 post implantation. However, despite the observed decrease in microglial density within the graft site, additional phenotypic analysis of graft-invading microglia, based on CD11b-and MHCII-expression, revealed >50% of graft-invading microglia at week 2 post implantation to display an activated status. Although microglial expression of CD11b and MHCII is already suggestive for a pro-inflammatory M1-oriented phenotype, the latter was further confirmed by: (i) the expression of NOS2 by microglia within the graft site, and (ii) the absence of arginase 1-expression, an enzyme known to suppress NO activity in M2-oriented microglia, on graft-surrounding and -invading microglia. In summary, we here provide a detailed phenotypic analysis of post transplantation innate immune events in the CNS of mice, and warrant that such intervention is associated with an M1-oriented microglia response and severe astrogliosis.
Journal of Neurosurgery, 1999
Object. Limitations regarding cell homogeneity and survivability do not affect neuronlike hNT cells, which are derived from a human teratocarcinoma cell line (Ntera2) that differentiates into postmitotic neurons with exposure to retinoic acid. Because NT2N neurons survive longer than 1 year after transplantation into nude mice brains, the authors grafted these cells into the brains of immunocompetent rats following lateral fluid-percussion brain injury to determine the long-term survivability of NT2N cell grafts in cortices damaged by traumatic brain injury (TBI) and the therapeutic effect of NT2N neurons on cognitive and motor deficits.Methods. Seventy-two adult male Sprague—Dawley rats, each weighing between 340 and 370 g, were given an anesthetic agent and subjected to lateral fluid percussion brain injury of moderate severity (2.2–2.5 atm in 46 rats) or to surgery without TBI (shamoperation, 26 rats). Twenty-four hours postinjury, 105 NT2N cells (24 injured animals) or 3 µl of v...
Spatiotemporal evolution of early innate immune responses triggered by neural stem cell grafting
Stem Cell Research & Therapy, 2012
Introduction: Transplantation of neural stem cells (NSCs) is increasingly suggested to become part of future therapeutic approaches to improve functional outcome of various central nervous system disorders. However, recently it has become clear that only a small fraction of grafted NSCs display long-term survival in the (injured) adult mouse brain. Given the clinical invasiveness of NSC grafting into brain tissue, profound characterisation and understanding of early post-transplantation events is imperative to claim safety and efficacy of cell-based interventions. Methods: Here, we applied in vivo bioluminescence imaging (BLI) and post-mortem quantitative histological analysis to determine the localisation and survival of grafted NSCs at early time points post-transplantation. Results: An initial dramatic cell loss (up to 80% of grafted cells) due to apoptosis could be observed within the first 24 hours post-implantation, coinciding with a highly hypoxic NSC graft environment. Subsequently, strong spatiotemporal microglial and astroglial cell responses were initiated, which stabilised by day 5 post-implantation and remained present during the whole observation period. Moreover, the increase in astrocyte density was associated with a high degree of astroglial scarring within and surrounding the graft site. During the two-week follow up in this study, the NSC graft site underwent extensive remodelling with NSC graft survival further declining to around 1% of the initial number of grafted cells. Conclusions: The present study quantitatively describes the early post-transplantation events following NSC grafting in the adult mouse brain and warrants that such intervention is directly associated with a high degree of cell loss, subsequently followed by strong glial cell responses.
2011
erative processes occurring under physiological (maintenance) and pathological (reparative) conditions are a fundamental part of life and vary greatly among different species, individuals, and tissues. Physiological regeneration occurs naturally as a consequence of normal cell erosion, or as an inevitable outcome of any biological process aiming at the restoration of homeostasis. Reparative regeneration occurs as a consequence of tissue damage. Although the central nervous system (CNS) has been considered for years as a "perennial" tissue, it has recently become clear that both physiological and reparative regeneration occur also within the CNS to sustain tissue homeostasis and repair. Proliferation and differentiation of neural stem/progenitor cells (NPCs) residing within the healthy CNS, or surviving injury, are considered crucial in sustaining these processes. Thus a large number of experimental stem cell-based transplantation systems for CNS repair have recently been established. The results suggest that transplanted NPCs promote tissue repair not only via cell replacement but also through their local contribution to changes in the diseased tissue milieu. This review focuses on the remarkable plasticity of endogenous and exogenous (transplanted) NPCs in promoting repair. Special attention will be given to the cross-talk existing between NPCs and CNS-resident microglia as well as CNS-infiltrating immune cells from the circulation, as a crucial event sustaining NPC-mediated neuroprotection. Finally, we will propose the concept of the context-dependent potency of transplanted NPCs (therapeutic plasticity) to exert multiple therapeutic actions, such as cell replacement, neurotrophic support, and immunomodulation, in CNS repair. I.
Journal of Trauma and Acute Care Surgery, 2019
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.