Sustained survival of xenografted human neural stem/progenitor cells in experimental brain trauma despite discontinuation of immunosuppression

Wennersten, André; Holmin, Staffan; Nimer, Faiez Al; Meijer, Xia; Wahlberg, Lars U.; Mathiesen, Tiit

doi:10.1016/j.expneurol.2005.12.035

Cited by 55 publications

(49 citation statements)

References 45 publications

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“…infused into rats (31). Several investigations suggest that T cell-mediated immune reaction plays a significant role in graft rejection and that interspecies incompatibility contributes significantly to phagocytosis of xenogeneic cells (32). Although xenoreactivity to human mesenchymal stem cells transplanted into infarcted rat myocardium has been demonstrated (33), these findings contrast with the results of Saito et al (34).…”

Section: Figure 2 (A)contrasting

confidence: 56%

Hemispheric Brain Injury and Behavioral Deficits Induced by Severe Neonatal Hypoxia-Ischemia in Rats Are Not Attenuated by Intravenous Administration of Human Umbilical Cord Blood Cells

et al. 2009

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Neonatal hypoxia-ischemia (HI) is an important cause of mortality and morbidity in infants. Human umbilical cord blood (HUCB) is a potential source of cellular therapy in perinatology. We investigated the effects of HUCB cells on spatial memory, motor performance, and brain morphologic changes in neonate rats submitted to HI. Seven-day-old rats underwent right carotid artery occlusion followed by exposure to 8% O 2 inhalation for 2 h. Twenty-four hours after HI, rats received either saline solution or HUCB cells i.v. After 3 wk, rats were assessed using a Morris Water Maze and four motor tests. Subsequently, rats were killed for histologic, immunohistochemical, and polymerase chain reaction (PCR) analyses. HI rats showed significant spatial memory deficits and a volumetric decrease in the hemisphere ipsilateral to arterial occlusion. These deficits and decreases were not significantly attenuated by the injection of HUCB cells. Moreover, immunofluorescence and PCR analysis revealed few HUCB cells located in rat brain. Intravenous administration of HUCB cells requires optimization to achieve improved therapeutic outcomes in neonatal hypoxic-ischemic injury. (Pediatr Res 65: 631-635, 2009) N eonatal hypoxia-ischemia (HI) is a major cause of mortality and morbidity in infants and occurs in approximately 2-4 per 1000 full-term births. Between 20 and 50% of asphyxiated newborns with hypoxic-ischemic encephalopathy die within the neonatal period, and up to 25% of the survivors will exhibit neurodevelopment morbidity, such as cerebral palsy, mental retardation, and epilepsy. The most widely used and accepted animal model of neonatal HI is the Levine method as modified by Rice et al. (1), which represents a useful tool to study long-term effects of neuroprotective strategies in behavioral changes, especially in learning and memory tasks (2). Although promising neuroprotective strategies have been studied in animal models and clinical trials, current management techniques have reached only limited success (3).Human umbilical cord blood (HUCB), is rich in adult stem cells and seems to be a potential source for transplantation, especially for perinatal neuronal repair. Studies have shown behavioral and neurologic recovery in stroke (4 -7) and HIinsulted animals (8,9) that received i.v. injection of HUCB, indicating that cells migrate toward ischemic regions and cross the blood brain barrier (BBB), especially in acute periods postischemia (10). The i.v. route is less invasive and a safer access to clinical applications when compared with intracerebral delivery. However, very few transplanted cells are found in the brain when delivered intravascularly. Therefore, evidence suggests that these cells increase endogenous mechanisms of brain repair by trophic factor secretion rather than by replacing the damaged tissue (11,12).The aim of this study was to assess the effects of HUCB cells on spatial memory, motor performance, and brain morphologic changes in 30-d-old rats after neonatal HI on postnatal d 7. In addition, w...

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Section: Figure 2 (A)contrasting

confidence: 56%

Hemispheric Brain Injury and Behavioral Deficits Induced by Severe Neonatal Hypoxia-Ischemia in Rats Are Not Attenuated by Intravenous Administration of Human Umbilical Cord Blood Cells

et al. 2009

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“…The successful use of transient immunosuppression proposes a suitable milder approach to immunosuppression for the prospective use of hNSCs for clinical purposes. The fact that the discontinuous treatment with cyclosporine does not affect integration of transplanted cells in most of the brain regions, which to all effects emerge as immunoprivileged when considering hNSCs, is in good accordance with most recent findings (Wennersten, et al 2006). These evidences are driving the progressive translation of the knowledge "from the bench to the bedside", thus leading to the use of hNSCs as a suitable tool to model transplantation in pre-clinical settings and to the promotion of GMP-grade hNSC for stem cell-mediated therapy of neurodegenerative disorders.…”

Section: Nsc-mediated Immunomodulation Of the Inflammatory Component supporting

confidence: 78%

“…This phenomenon may, in fact, participate in the low immunogenic response that these cells seem to elicit in the CNS, together with the lack of expression of Molecular Histocompatibility Complex class II components (MHCII) (Imitola et al 2004a;Imitola, et al 2004b)(see also Fig 1). Notwithstanding, it is also true that some level of immune surveillance is maintained in the adult brain upon NSC engraftment, which explains the widespread need to use immune suppression (Wennersten, et al 2006) in experimental and clinical intracerebral transplantation (Bjorklund, et al 2003;Olstorn, et al 2007). The successful use of transient immunosuppression proposes a suitable milder approach to immunosuppression for the prospective use of hNSCs for clinical purposes.…”

Section: Nsc-mediated Immunomodulation Of the Inflammatory Component mentioning

confidence: 99%

“…Notably, these results could be accomplished using transient immunosuppression, i.e administering cyclosporine for 15 days following the ischemic event. A wide array of studies have shown that NSCs are not susceptible to immunological rejection (Bjorklund et al 2003;Mendez et al 2008;Olstorn et al 2007;Wennersten et al 2006) even when transplanted in animal models like EAE, characterized by a constitutively activated immunological response (Pluchino, et al 2003;Pluchino, et al 2005). Similar results were also obtained in a different context: after transplantation into the adult rat brain lesioned by focal demyelination (Ferrari et al, submitted), hNSCs demonstrated to integrate into the NSC host niche and to migrate toward the lesioned corpus callosum, where they properly differentiated into myelinating oligodendrocytes.…”

Section: Low Immunogenic Potential Of Nscmentioning

confidence: 99%

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Low Immunogenic Potential of Human Neural Stem Cells

Filippis¹,

Nodari²,

Gelati³

2012

Immunosuppression - Role in Health and Diseases

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“…21 Human NSCs have been shown to survive in the brain after discontinuation of immunosuppression. 75 This could be particularly important, given the current controversy surrounding the immune response to these cells and whether it may be safe to administer nonautologous cells to patients. One explanation for the possible immunoprivileged nature of human NSCs is the downregulation of major histocompatibility expression.…”

Section: Neural Stem Cell Therapymentioning

confidence: 99%

Cell therapies for traumatic brain injury

Harting

Baumgartner

Worth

et al. 2008

FOC

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Preliminary discoveries of the efficacy of cell therapy are currently being translated to clinical trials. Whereas a significant amount of work has been focused on cell therapy applications for a wide array of diseases, including cardiac disease, bone disease, hepatic disease, and cancer, there continues to be extraordinary anticipation that stem cells will advance the current therapeutic regimen for acute neurological disease. Traumatic brain injury is a devastating event for which current therapies are limited. In this report the authors discuss the current status of using adult stem cells to treat traumatic brain injury, including the basic cell types and potential mechanisms of action, preclinical data, and the initiation of clinical trials.

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Sustained survival of xenografted human neural stem/progenitor cells in experimental brain trauma despite discontinuation of immunosuppression

Cited by 55 publications

References 45 publications

Hemispheric Brain Injury and Behavioral Deficits Induced by Severe Neonatal Hypoxia-Ischemia in Rats Are Not Attenuated by Intravenous Administration of Human Umbilical Cord Blood Cells

Hemispheric Brain Injury and Behavioral Deficits Induced by Severe Neonatal Hypoxia-Ischemia in Rats Are Not Attenuated by Intravenous Administration of Human Umbilical Cord Blood Cells

Low Immunogenic Potential of Human Neural Stem Cells

Cell therapies for traumatic brain injury

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