The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Andreina Schoeberlein - One of the best experts on this subject based on the ideXlab platform.
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One Step Closer to Remyelination after Perinatal Brain Damage: Wharton’s Jelly Mesenchymal Stem Cell-Derived Exosomes Drive Neural Progenitors towards Oligodendroglial Cell Fate
2018Co-Authors: Marianne Jörger Messerli, Marialuigia Spinelli, Byron Oppliger, Gierin Florence Thomi, Valérie Haesler, Daniel Surbek, Andreina SchoeberleinAbstract:INTRODUCTION: The loss of oligodendrocyte progenitor cells leading to overall hypomyelination of the Brain is a major hallmark in Perinatal Brain Damage. Experimental transplantations of mesenchymal stem cells (MSC) in animal models of Perinatal Brain Damage strongly indicate that the regenerative effects rely on released factors such as MSC-derived exosomes. METHODS: Thus, the aim of this study is to investigate the capacity of exosomes from human Wharton’s jelly-derived MSC (WJ-MSC) to determine neural progenitor cells (NPC) towards oligodendroglial cell fate. WJ-MSC-derived exosomes were isolated from culture supernatants by serial high-speed and ultracentrifugations. Exosome microRNA (miRNA) content was assessed by real-time PCR. After 72 h of co-culture with WJ-MSC-derived EV, NPC were evaluated for the expression of markers involved in oligodendroglial specification and differentiation by real-time PCR. RESULTS: miRNA that are involved in oligodendroglial cell fate specification and differentiation (miR-338, miR-9, miR-19b, miR-138) were present in WJ-MSC-derived exosomes. The expression of miR-338-3p, known to trigger oligodendrocyte specification, was significantly increased in NPC after co-culture with exosomes. In addition, the gene expression of the transcription factor neurogenic differentiation factor 1 (Neurod1), which blocks oligodendrogenic specification and is repressed by miR-338, was significantly reduced in NPC after co-culture with exosomes. Furthermore, the gene expression of the transcription factor Hairy and enhancer of split (HES1) induced by the Notch signaling pathway, which is activated during oligodendroglial specification, was significantly elevated in NPC after incubation with exosomes. CONCLUSION: In conclusion, isolated WJ-MSC-derived exosomes expressed miRNA having key roles in oligodendrogenesis. Exosomes induced NPC towards oligodendroglial cell fate, ascribing a promising role in neuroregeneration to WJ-MSC-derived exosomes. Financial support by Gottfried and Julia Bangerter-Rhyner Foundation
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one step closer to remyelination after Perinatal Brain Damage wharton s jelly mesenchymal stem cell derived exosomes drive neural progenitors towards oligodendroglial cell fate
2018Co-Authors: Marianne Jörger Messerli, Marialuigia Spinelli, Byron Oppliger, Gierin Florence Thomi, Valérie Haesler, Daniel Surbek, Andreina SchoeberleinAbstract:INTRODUCTION: The loss of oligodendrocyte progenitor cells leading to overall hypomyelination of the Brain is a major hallmark in Perinatal Brain Damage. Experimental transplantations of mesenchymal stem cells (MSC) in animal models of Perinatal Brain Damage strongly indicate that the regenerative effects rely on released factors such as MSC-derived exosomes. METHODS: Thus, the aim of this study is to investigate the capacity of exosomes from human Wharton’s jelly-derived MSC (WJ-MSC) to determine neural progenitor cells (NPC) towards oligodendroglial cell fate. WJ-MSC-derived exosomes were isolated from culture supernatants by serial high-speed and ultracentrifugations. Exosome microRNA (miRNA) content was assessed by real-time PCR. After 72 h of co-culture with WJ-MSC-derived EV, NPC were evaluated for the expression of markers involved in oligodendroglial specification and differentiation by real-time PCR. RESULTS: miRNA that are involved in oligodendroglial cell fate specification and differentiation (miR-338, miR-9, miR-19b, miR-138) were present in WJ-MSC-derived exosomes. The expression of miR-338-3p, known to trigger oligodendrocyte specification, was significantly increased in NPC after co-culture with exosomes. In addition, the gene expression of the transcription factor neurogenic differentiation factor 1 (Neurod1), which blocks oligodendrogenic specification and is repressed by miR-338, was significantly reduced in NPC after co-culture with exosomes. Furthermore, the gene expression of the transcription factor Hairy and enhancer of split (HES1) induced by the Notch signaling pathway, which is activated during oligodendroglial specification, was significantly elevated in NPC after incubation with exosomes. CONCLUSION: In conclusion, isolated WJ-MSC-derived exosomes expressed miRNA having key roles in oligodendrogenesis. Exosomes induced NPC towards oligodendroglial cell fate, ascribing a promising role in neuroregeneration to WJ-MSC-derived exosomes. Financial support by Gottfried and Julia Bangerter-Rhyner Foundation
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Intranasal Delivery of Umbilical Cord-Derived Mesenchymal Stem Cells Preserves Myelination in Perinatal Brain Damage.
Stem cells and development, 2016Co-Authors: Byron Oppliger, Daniel Surbek, Marianne Joerger-messerli, Martin Mueller, Ursula Reinhart, Philipp Schneider, Andreina SchoeberleinAbstract:Preterm white matter injury (WMI) is an important cause for long-term disability. Stem cell transplantation has been proposed as a novel therapeutic approach. However, intracerebral transplantation is not feasible for clinical purpose in newborns. Intranasal delivery of cells to the Brain might be a promising, noninvasive therapeutic approach to restore the Damaged Brain. Therefore, our goal is to study the remyelinating potential of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) after intranasal delivery. Wistar rat pups, previously Brain-Damaged by a combined hypoxic-ischemic and inflammatory insult, received hWJ-MSC (150,000 cells in 3 μL) that were intranasally delivered twice to each nostril (600,000 cells total). WMI was assessed by immunohistochemistry and western blot for myelination, astrogliosis, and microgliosis. The expression of preoligodendrocyte markers, and neurotrophic factors, was analyzed by real-time polymerase chain reaction. Animals treated with intranasally delivered hWJ-MSC showed increased myelination and decreased gliosis compared to untreated animals. hWJ-MSC may, therefore, modulate the activation of microglia and astrocytes, resulting in a change of the Brain microenvironment, which facilitates the maturation of oligodendrocyte lineage cells. This is the first study to show that intranasal delivery of hWJ-MSC in rats prevented hypomyelination and microgliosis in a model of WMI in the premature rat Brain. Further studies should address the dose and frequency of administration.
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53 successful transnasal delivery of stem cells in a rat model of Perinatal hypoxic ischemic Brain injury
American Journal of Obstetrics and Gynecology, 2015Co-Authors: Byron Oppliger, Andreina Schoeberlein, Ursula Reinhart, Martin Muller, Marianne Jorgermesserli, Daniel SurbekAbstract:OBJECTIVE: New routes for cell transplantation into the Brain need to be explored as intracerebral or intrathecal applications have a high risk to cause Damage to the central nervous system. It has been hypothesized that transnasally administrated cells bypass the blood-Brain barrier and migrate along the olfactory neural route into the Brain and cerebrospinal fluid. Our goal is to confirm this hypothesis by transnasally administrating Wharton’s Jelly mesenchymal stem cells (WJ-MSC) and neural progenitor cells (NPC) to Perinatal rats in a model of hypoxic-ischemic Brain injury. STUDY DESIGN: Four-day-old Wistar rat pups, previously Brain-Damaged by combined hypoxic-ischemic and inflammatory insult, either received WJ-MSC or green fluorescent protein-expressing NPC: The heads of the rat pups were immobilized and 3 ml drops containing the cells (50’000 cells/ml) were placed on one nostril allowing it to be snorted. This procedure was repeated twice, alternating right to left nostril with an interval of one minute between administrations. The rat pups received a total of 600’000 cells. Animals were sacrificed 24h, 48h or 7 days after the application of the cells. Fixed Brains were collected, embedded in paraffin and sectioned. RESULTS: Transplanted cells were found in the layers of the olfactory bulb (OB), the cerebral cortex, thalamus and the hippocampus. The amount of cells was highest in the OB. Animals treated with transnasally delivered stem cells showed significantly decreased gliosis compared to untreated animals. CONCLUSION: Our data show that transnasal delivery of WJ-MSC and NPC to the newborn Brain after Perinatal Brain Damage is successful. The cells not only migrate the Brain, but also decrease scar formation and improve neurogenesis. Therefore, the non-invasive intranasal delivery of stem cells to the Brain may be the preferred method for stem cell treatment of Perinatal Brain Damage and should be preferred in future clinical trials.
Thalía Harmony - One of the best experts on this subject based on the ideXlab platform.
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Long-term therapeutic effects of Katona therapy in moderate-to-severe Perinatal Brain Damage.
Neuroscience letters, 2020Co-Authors: Manuel Hinojosa-rodríguez, José Oliver De Leo Jiménez, María Elena Juárez Colín, Eduardo Gonzalez Moreira, Carlos Sair Flores Bautista, Thalía HarmonyAbstract:Abstract Aim To determine the long-term efficacy of Katona therapy and early rehabilitation of infants with moderate-to-severe Perinatal Brain Damage (PBD). Methods Thirty-two participants were recruited (7–16 years) and divided into 3 groups: one Healthy group (n = 11), one group with PBD treated with Katona methodology from 2 months of corrected age, and with long-term follow-up (n = 12), and one group with PBD but without treatment in the first year of life due to late diagnosis of PBD (n = 9). Neuropediatric evaluations, motor evoked potentials (MEPs) and magnetic resonance images (MRI) were made. The PBD groups were matched by severity and topography of lesion. Results The patients treated with Katona had better motor performance when compared to patients without early treatment (Gross Motor Function Classification System levels; 75% of Katona group were classified in levels I and II and 78% of patients without early treatment were classified in levels III and IV). Furthermore, independent k-means cluster analyses of MRI, MEPs, and neuropediatric evaluations data were performed. Katona and non-treated early groups were classified in the same MRI cluster which is the expected for PBD population patients. However, in MEPs and neuropediatric evaluations clustering, the 67% of Katona group were assigned into Healthy group showing the impact of Katona therapy over the patients treated with it. These results highlight the Katona therapy benefits in early rehabilitation of infants with moderate-to-severe PBD. Conclusions Katona therapy and early rehabilitation have an important therapeutic effect in infants with moderate-to-severe PBD by decreasing the severity of motor disability in later stages of life.
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Long-Term therapeutic effects of Katona therapy in moderate-to-severe Perinatal Brain Damage
arXiv: Neurons and Cognition, 2020Co-Authors: Manuel Hinojosa-rodríguez, Maria Elena Juarez-colin, José Oliver De Leo Jiménez, Eduardo Gonzalez-moreira, Carlos Sair Flores-bautista, Thalía HarmonyAbstract:Aim: To determine the long-term efficacy of Katona therapy and early rehabilitation of infants with moderate-to-severe Perinatal Brain Damage (PBD). Methods: Thirty-two participants were recruited (7-to-16 years) and divided into 3 groups: one Healthy group (n = 11), one group with PBD treated with Katona methodology from 2 months of corrected age, and with long-term follow-up (n = 12), and one group with PBD but without treatment in the first year of life due to late diagnosis of PBD (n = 9). Neuropediatric evaluations, motor evoked potentials (MEPs) and magnetic resonance images (MRI) were made. The PBD groups were matched by severity and topography of lesion. Results: The patients treated with Katona had better motor performance when compared to patients without early treatment (Gross Motor Function Classification System levels; 75% of Katona group were classified in levels I and II and 78% of patients without early treatment were classified in levels III and IV). Furthermore, independent k-means cluster analyses of MRI, MEPs, and neuropediatric evaluations data were performed. Katona and non-treated early groups were classified in the same MRI cluster which is the expected for patient's population with PBD. However, in MEPs and neuropediatric evaluations clustering, the 67% of Katona group were assigning into Healthy group showing the impact of Katona therapy over the patients treated with it. These results highlight the Katona therapy benefits in early rehabilitation of infants with moderate-to-severe PBD. Conclusions: Katona therapy and early rehabilitation have an important therapeutic effect in infants with moderate-to-severe PBD by decreasing the severity of motor disability in later stages of life.
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Longitudinal study of children with Perinatal Brain Damage in whom early neurohabilitation was applied: Preliminary report
Neuroscience letters, 2015Co-Authors: Thalía Harmony, Jesús Barrera-reséndiz, Maria Elena Juarez-colin, Cristina Carrillo-prado, M. Del Consuelo Pedraza-aguilar, Aurora Asprón Ramírez, Manuel Hinojosa-rodríguez, Thalía Fernández, Josefina Ricardo-garcellAbstract:Abstract Objective The neurohabilitation treatment has been shown to be a successful method for decreasing the sequelae of Perinatal Brain Damage (PBD) in Hungarian population. The goal of this pilot trial was to introduce this procedure by describing the results of its application in infants with PBD as demonstrated by clinical, developmental and MRI studies. As this procedure has proved to be useful, according the declaration of Helsinki, no control clinical trial was permitted. Participants Infants younger than 2 months of corrected age (CA) with prenatal and/or Perinatal risk factors for Brain Damage. Two groups were considered. One group was treated using the “neurohabilitation” method ( n = 20), and the other was not treated ( n = 13) because treatment was voluntarily discontinued after the initial evaluation. Evaluations were carried out prior to 2 months of CA and at 6–8 years of age. All children showed abnormal clinical and MRI characteristics in the first study. Results The treated group had a higher percentage (90%) of children with normal outcome than did the non-treated group (38%; OR = 2.37, CI 95% = 1.2–4.7; p p = 0.017). Conclusions This pilot trial confirms previous studies suggesting that Neurohabilitation decreases the neurological and cognitive sequelae of preterm and at-term infants with PBD.
Alan Leviton - One of the best experts on this subject based on the ideXlab platform.
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Endoplasmic Reticulum Stress, Inflammation, and Perinatal Brain Damage
Pediatric Research, 2009Co-Authors: Wolfgang Bueter, Olaf Dammann, Alan LevitonAbstract:Inflammation seems to play a role in the pathogenesis of Perinatal Brain Damage in fetuses/infants born much before term. We raise the possibility that noninflammatory phenomena induce endoplasmic reticulum stress, which, in turn, leads to the unfolded protein response, which is followed by apoptosis-promoting processes and inflammation. Perhaps by these events, noninflammatory stimuli lead to Perinatal Brain Damage.
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Neuregulin-1: a potential endogenous protector in Perinatal Brain white matter Damage
Neonatology, 2007Co-Authors: Olaf Dammann, Wolfgang Bueter, Alan Leviton, Pierre Gressens, Christiane E.l. DammannAbstract:Brain white matter Damage, an important antecedent of long-term disabilities among preterm infants, has both endogenous and exogenous components. One of the endogenous components is the paucity of developmentally regulated protectors. Here we expand on this component, discussing the potential roles of one putative protector, neuregulin (NRG)-1, in Brain development and Damage. We outline how NRG-1 might be involved in Perinatal Brain Damage pathomechanisms and suggest that NRG-1 might be one target for intervention.
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Perinatal Brain Damage causation.
Developmental neuroscience, 2007Co-Authors: Olaf Dammann, Alan LevitonAbstract:The search for causes of Perinatal Brain Damage needs a solid theoretical foundation. Current theory apparently does not offer a unanimously accepted view of what constitutes a cause, and how it can be identified. We discuss nine potential theoretical misconceptions: (1) too narrow a view of what is a cause (causal production vs. facilitation), (2) extrapolating from possibility to fact (potential vs. factual causation), (3) if X, then invariably Y (determinism vs. probabilism), (4) co-occurrence in individuals vs. association in populations, (5) one cause is all that is needed (single cause attribution vs. multicausal constellations), (6) drawing causal inferences from very small numbers of observations (the tendency to generalize), (7) unstated causal inferences, (8) ignoring heterogeneity, and (9) failing to consider alternative explanations for what is observed. We hope that our critical discussion will contribute to fruitful research and help reduce the burden of Perinatal Brain Damage.
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Adult stroke and Perinatal Brain Damage: Like grandparent, like grandchild?
Neuropediatrics, 2002Co-Authors: Alan Leviton, Olaf Dammann, T M O'shea, Nigel PanethAbstract:Biomarkers of inflammation are found in the circulation of adults who have had a stroke. Although these biomarkers may, in part, be indicators of Damage, some appear to contribute to Damage. Similar biomarkers are found in newborns with cerebral white matter Damage or at risk of cerebral palsy. Can we learn about the pathogenesis of neonatal white matter Damage from what has been learned about the inflammatory correlates of adult stroke? We discuss relevant findings about systemic inflammatory markers in adult stroke and relate this information to our current understanding of cerebral white matter Damage in newborns, especially those born at an extremely low gestational age. We also describe desirable characteristics of future studies of Perinatal Brain Damage that involve measurements of systemic biomarkers.
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The role of Perinatal Brain Damage in developmental disabilities: An epidemiologic perspective
Mental Retardation and Developmental Disabilities Research Reviews, 1997Co-Authors: Olaf Dammann, Alan LevitonAbstract:To examine the potential contribution of epidemiologic research to the identification of Perinatal Brain Damage as a “cause” of developmental disabilities, the authors review definitions and methods used in this field. The current literature provides considerably different estimates of the population prevalence of mental retardation (3–40 per thousand), cerebral palsy (1.2–2.6 per thousand), and learning disabilities (33–65 per thousand). Furthermore, the presumable proportion of disabilities caused in the Perinatal period also differs with the population under investigation, age at examination, and exposure and outcome definition. Approximately 8–43% of cerebral palsy and 10–25% of mental retardation may be associated with variables describing Perinatal morbidity usually interpreted as indicators of Brain Damage. The authors discuss the recent literature on the association of developmental disabilities and proxy variables, e.g., abnormal neuroimaging results, so-called asphyxia, abnormal fetal heart rate patterns or thyroxine levels, and severity of illness scores. Exact definitions of exposure and outcome, a proper study design, and agreement of findings from multiple studies are needed before associations between Perinatal Brain Damage and developmental disabilities should be accepted as causal. MRDD Research Reviews 3:13–21, 1997. © 1997 Wiley-Liss, Inc.
Olaf Dammann - One of the best experts on this subject based on the ideXlab platform.
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Toward Multi-Scale Computational Modeling in Developmental Disability Research
Neuropediatrics, 2011Co-Authors: Olaf Dammann, Pamela L. FollettAbstract:The field of theoretical neuroscience is gaining increasing recognition. Virtually all areas of neuroscience offer potential linkage points for computational work. In developmental neuroscience, main areas of research are neural development and connectivity, and connectionist modeling of cognitive development. In this paper, we suggest that computational models can be helpful tools for understanding the pathogenesis and consequences of Perinatal Brain Damage and subsequent developmental disability. In particular, designing multi-scale computational models should be considered by developmental neuroscientists interested in helping reduce the risk for developmental disabilities.
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Endoplasmic Reticulum Stress, Inflammation, and Perinatal Brain Damage
Pediatric Research, 2009Co-Authors: Wolfgang Bueter, Olaf Dammann, Alan LevitonAbstract:Inflammation seems to play a role in the pathogenesis of Perinatal Brain Damage in fetuses/infants born much before term. We raise the possibility that noninflammatory phenomena induce endoplasmic reticulum stress, which, in turn, leads to the unfolded protein response, which is followed by apoptosis-promoting processes and inflammation. Perhaps by these events, noninflammatory stimuli lead to Perinatal Brain Damage.
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Cytokines and Perinatal Brain Damage.
Clinics in perinatology, 2008Co-Authors: Olaf Dammann, T. Michael O'sheaAbstract:Perinatal Brain Damage has been implicated in the pathogenesis of neurodevelopmental impairments and psychiatric illnesses. This article reviews evidence that infection outside of the Brain can Damage the Brain, and discusses specific cytokines and pathomechanisms that probably mediate the putative effect of remote infection on the developing Brain. Events associated with increased circulating inflammatory cytokines, chemokines, and immune cells are described. Finally, studies of genetic variation in susceptibility to cytokine-related Brain Damage are reviewed.
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Neuregulin-1: a potential endogenous protector in Perinatal Brain white matter Damage
Neonatology, 2007Co-Authors: Olaf Dammann, Wolfgang Bueter, Alan Leviton, Pierre Gressens, Christiane E.l. DammannAbstract:Brain white matter Damage, an important antecedent of long-term disabilities among preterm infants, has both endogenous and exogenous components. One of the endogenous components is the paucity of developmentally regulated protectors. Here we expand on this component, discussing the potential roles of one putative protector, neuregulin (NRG)-1, in Brain development and Damage. We outline how NRG-1 might be involved in Perinatal Brain Damage pathomechanisms and suggest that NRG-1 might be one target for intervention.
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Anti-inflammatory and immunomodulatory strategies to protect the Perinatal Brain.
Seminars in fetal & neonatal medicine, 2007Co-Authors: Adam Wolfberg, Olaf Dammann, Pierre GressensAbstract:Infection and inflammation contribute to Perinatal Brain Damage, particularly to the white matter. Although combating Perinatal inflammation can be dangerous, because inflammation might have beneficial effects for mother and fetus, it is worthwhile reviewing potential anti-inflammatory neuroprotective compounds, along with their potential adverse effects. Further research on the possible neuroprotective roles of existing medications and substances is necessary.
Daniel Surbek - One of the best experts on this subject based on the ideXlab platform.
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One Step Closer to Remyelination after Perinatal Brain Damage: Wharton’s Jelly Mesenchymal Stem Cell-Derived Exosomes Drive Neural Progenitors towards Oligodendroglial Cell Fate
2018Co-Authors: Marianne Jörger Messerli, Marialuigia Spinelli, Byron Oppliger, Gierin Florence Thomi, Valérie Haesler, Daniel Surbek, Andreina SchoeberleinAbstract:INTRODUCTION: The loss of oligodendrocyte progenitor cells leading to overall hypomyelination of the Brain is a major hallmark in Perinatal Brain Damage. Experimental transplantations of mesenchymal stem cells (MSC) in animal models of Perinatal Brain Damage strongly indicate that the regenerative effects rely on released factors such as MSC-derived exosomes. METHODS: Thus, the aim of this study is to investigate the capacity of exosomes from human Wharton’s jelly-derived MSC (WJ-MSC) to determine neural progenitor cells (NPC) towards oligodendroglial cell fate. WJ-MSC-derived exosomes were isolated from culture supernatants by serial high-speed and ultracentrifugations. Exosome microRNA (miRNA) content was assessed by real-time PCR. After 72 h of co-culture with WJ-MSC-derived EV, NPC were evaluated for the expression of markers involved in oligodendroglial specification and differentiation by real-time PCR. RESULTS: miRNA that are involved in oligodendroglial cell fate specification and differentiation (miR-338, miR-9, miR-19b, miR-138) were present in WJ-MSC-derived exosomes. The expression of miR-338-3p, known to trigger oligodendrocyte specification, was significantly increased in NPC after co-culture with exosomes. In addition, the gene expression of the transcription factor neurogenic differentiation factor 1 (Neurod1), which blocks oligodendrogenic specification and is repressed by miR-338, was significantly reduced in NPC after co-culture with exosomes. Furthermore, the gene expression of the transcription factor Hairy and enhancer of split (HES1) induced by the Notch signaling pathway, which is activated during oligodendroglial specification, was significantly elevated in NPC after incubation with exosomes. CONCLUSION: In conclusion, isolated WJ-MSC-derived exosomes expressed miRNA having key roles in oligodendrogenesis. Exosomes induced NPC towards oligodendroglial cell fate, ascribing a promising role in neuroregeneration to WJ-MSC-derived exosomes. Financial support by Gottfried and Julia Bangerter-Rhyner Foundation
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one step closer to remyelination after Perinatal Brain Damage wharton s jelly mesenchymal stem cell derived exosomes drive neural progenitors towards oligodendroglial cell fate
2018Co-Authors: Marianne Jörger Messerli, Marialuigia Spinelli, Byron Oppliger, Gierin Florence Thomi, Valérie Haesler, Daniel Surbek, Andreina SchoeberleinAbstract:INTRODUCTION: The loss of oligodendrocyte progenitor cells leading to overall hypomyelination of the Brain is a major hallmark in Perinatal Brain Damage. Experimental transplantations of mesenchymal stem cells (MSC) in animal models of Perinatal Brain Damage strongly indicate that the regenerative effects rely on released factors such as MSC-derived exosomes. METHODS: Thus, the aim of this study is to investigate the capacity of exosomes from human Wharton’s jelly-derived MSC (WJ-MSC) to determine neural progenitor cells (NPC) towards oligodendroglial cell fate. WJ-MSC-derived exosomes were isolated from culture supernatants by serial high-speed and ultracentrifugations. Exosome microRNA (miRNA) content was assessed by real-time PCR. After 72 h of co-culture with WJ-MSC-derived EV, NPC were evaluated for the expression of markers involved in oligodendroglial specification and differentiation by real-time PCR. RESULTS: miRNA that are involved in oligodendroglial cell fate specification and differentiation (miR-338, miR-9, miR-19b, miR-138) were present in WJ-MSC-derived exosomes. The expression of miR-338-3p, known to trigger oligodendrocyte specification, was significantly increased in NPC after co-culture with exosomes. In addition, the gene expression of the transcription factor neurogenic differentiation factor 1 (Neurod1), which blocks oligodendrogenic specification and is repressed by miR-338, was significantly reduced in NPC after co-culture with exosomes. Furthermore, the gene expression of the transcription factor Hairy and enhancer of split (HES1) induced by the Notch signaling pathway, which is activated during oligodendroglial specification, was significantly elevated in NPC after incubation with exosomes. CONCLUSION: In conclusion, isolated WJ-MSC-derived exosomes expressed miRNA having key roles in oligodendrogenesis. Exosomes induced NPC towards oligodendroglial cell fate, ascribing a promising role in neuroregeneration to WJ-MSC-derived exosomes. Financial support by Gottfried and Julia Bangerter-Rhyner Foundation
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Intranasal Delivery of Umbilical Cord-Derived Mesenchymal Stem Cells Preserves Myelination in Perinatal Brain Damage.
Stem cells and development, 2016Co-Authors: Byron Oppliger, Daniel Surbek, Marianne Joerger-messerli, Martin Mueller, Ursula Reinhart, Philipp Schneider, Andreina SchoeberleinAbstract:Preterm white matter injury (WMI) is an important cause for long-term disability. Stem cell transplantation has been proposed as a novel therapeutic approach. However, intracerebral transplantation is not feasible for clinical purpose in newborns. Intranasal delivery of cells to the Brain might be a promising, noninvasive therapeutic approach to restore the Damaged Brain. Therefore, our goal is to study the remyelinating potential of human Wharton's jelly mesenchymal stem cells (hWJ-MSCs) after intranasal delivery. Wistar rat pups, previously Brain-Damaged by a combined hypoxic-ischemic and inflammatory insult, received hWJ-MSC (150,000 cells in 3 μL) that were intranasally delivered twice to each nostril (600,000 cells total). WMI was assessed by immunohistochemistry and western blot for myelination, astrogliosis, and microgliosis. The expression of preoligodendrocyte markers, and neurotrophic factors, was analyzed by real-time polymerase chain reaction. Animals treated with intranasally delivered hWJ-MSC showed increased myelination and decreased gliosis compared to untreated animals. hWJ-MSC may, therefore, modulate the activation of microglia and astrocytes, resulting in a change of the Brain microenvironment, which facilitates the maturation of oligodendrocyte lineage cells. This is the first study to show that intranasal delivery of hWJ-MSC in rats prevented hypomyelination and microgliosis in a model of WMI in the premature rat Brain. Further studies should address the dose and frequency of administration.
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53 successful transnasal delivery of stem cells in a rat model of Perinatal hypoxic ischemic Brain injury
American Journal of Obstetrics and Gynecology, 2015Co-Authors: Byron Oppliger, Andreina Schoeberlein, Ursula Reinhart, Martin Muller, Marianne Jorgermesserli, Daniel SurbekAbstract:OBJECTIVE: New routes for cell transplantation into the Brain need to be explored as intracerebral or intrathecal applications have a high risk to cause Damage to the central nervous system. It has been hypothesized that transnasally administrated cells bypass the blood-Brain barrier and migrate along the olfactory neural route into the Brain and cerebrospinal fluid. Our goal is to confirm this hypothesis by transnasally administrating Wharton’s Jelly mesenchymal stem cells (WJ-MSC) and neural progenitor cells (NPC) to Perinatal rats in a model of hypoxic-ischemic Brain injury. STUDY DESIGN: Four-day-old Wistar rat pups, previously Brain-Damaged by combined hypoxic-ischemic and inflammatory insult, either received WJ-MSC or green fluorescent protein-expressing NPC: The heads of the rat pups were immobilized and 3 ml drops containing the cells (50’000 cells/ml) were placed on one nostril allowing it to be snorted. This procedure was repeated twice, alternating right to left nostril with an interval of one minute between administrations. The rat pups received a total of 600’000 cells. Animals were sacrificed 24h, 48h or 7 days after the application of the cells. Fixed Brains were collected, embedded in paraffin and sectioned. RESULTS: Transplanted cells were found in the layers of the olfactory bulb (OB), the cerebral cortex, thalamus and the hippocampus. The amount of cells was highest in the OB. Animals treated with transnasally delivered stem cells showed significantly decreased gliosis compared to untreated animals. CONCLUSION: Our data show that transnasal delivery of WJ-MSC and NPC to the newborn Brain after Perinatal Brain Damage is successful. The cells not only migrate the Brain, but also decrease scar formation and improve neurogenesis. Therefore, the non-invasive intranasal delivery of stem cells to the Brain may be the preferred method for stem cell treatment of Perinatal Brain Damage and should be preferred in future clinical trials.