| 1. |
- Ahlenius, Henrik, et al.
(author)
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Adaptor Protein LNK Is a Negative Regulator of Brain Neural Stem Cell Proliferation after Stroke.
- 2012
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In: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:15, s. 5151-5164
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Journal article (peer-reviewed)abstract
- Ischemic stroke causes transient increase of neural stem and progenitor cell (NSPC) proliferation in the subventricular zone (SVZ), and migration of newly formed neuroblasts toward the damaged area where they mature to striatal neurons. The molecular mechanisms regulating this plastic response, probably involved in structural reorganization and functional recovery, are poorly understood. The adaptor protein LNK suppresses hematopoietic stem cell self-renewal, but its presence and role in the brain are poorly understood. Here we demonstrate that LNK is expressed in NSPCs in the adult mouse and human SVZ. Lnk(-/-) mice exhibited increased NSPC proliferation after stroke, but not in intact brain or following status epilepticus. Deletion of Lnk caused increased NSPC proliferation while overexpression decreased mitotic activity of these cells in vitro. We found that Lnk expression after stroke increased in SVZ through the transcription factors STAT1/3. LNK attenuated insulin-like growth factor 1 signaling by inhibition of AKT phosphorylation, resulting in reduced NSPC proliferation. Our findings identify LNK as a stroke-specific, endogenous negative regulator of NSPC proliferation, and suggest that LNK signaling is a novel mechanism influencing plastic responses in postischemic brain.
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| 2. |
- Ahlenius, Henrik
(author)
-
Adult Neural Stem Cells-Influence of Stroke, Inflammation and Aging
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Neural stem cells (NSCs) in the embryo generate neurons, astrocytes and oligodendrocytes, the principal cells of the central nervous system (CNS), which contribute to the full diversity of the brain. Some NSCs persist in the adult brain and ensures neurogenesis throughout adult life in the subventricular zone (SVZ) and the subgranular zone (SGZ). NSCs in the SGZ generates neurons in the granule cell layer and NSCs in the SVZ generates neuroblasts that migrate trough the rostral migratory stream into the olfactory bulb where they develop into mature neurons. Neurogenesis in the adult brain continues into old age although with reduced capacity. Neurogenesis in SVZ increases after insults to the brain such as stroke and status epilepticus (SE). After stroke proliferation of NSCs increase and newly formed neurons migrate towards the damage where they mature into the same type of neurons that died as a result of the insult. This self-repair mechanism could potentially be of therapeutic value. However, existing neurogenesis as basis for functional recovery after stroke is most likely not sufficient. Therefore, it is extremely important to study regulation of basal and insult induced neurogenesis in order to find ways of optimizing the potential of endogenous NSCs for repair of neurodegenerative disease. In this thesis we have addressed the regulation of adult NSCs and neurogenesis in response to aging, inflammation and stroke using in vivo and in vitro models as well as gene expression analysis. In the first study we explored the influence of aging on intrinsic properties of NSCs and their progeny. We found severely decreased neurogenesis in old mice due to reduced proliferation and loss of NSCs in SVZ. However, when we cultured aged NSC in vitro they could proliferate, differentiate along all three lineages and produce functional neurons similar to their adult counterparts albeit with reduced capacity. In the second study, we investigated the role of inflammation on stroke-induced neurogenesis. More specifically we identified tumor necrosis factor receptor 1 (TNF-R1) as a negative regulator of Stroke-induced NSC proliferation in SVZ. We found increased expression of TNF-α and TNF-R1 in SVZ after stroke. Furthermore we demonstrated a direct negative effect of TNF-α through TNF-R1 on proliferation of NSCs in vitro. In the third study, we identified the adaptor protein Lnk as an insult specific negative regulator of NSC proliferation. Possibly acting by inhibiting growth factor and cytokine signaling. Deletion of Lnk increased the enhanced proliferation in SVZ after stroke but not under basal condition or after SE. We found increased expression of Lnk and growth factors in SVZ after stroke but decreased expression after SE. Furthermore elevated levels of Lnk decreased proliferation and survival while deletion of Lnk increased the proliferation of NSCs in vitro. In summary, we have obtained evidence supporting that brain-repair from endogenous NSCs can work in old age. Furthermore, we have identified two potential therapeutic targets for enhancing neurogenesis after stroke.
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| 3. |
- Ahlenius, Henrik, et al.
(author)
-
Chinese and Westerners Respond Differently to the Trolley Dilemmas
- 2012
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In: Journal of Cognition and Culture. - : Brill. - 1567-7095 .- 1568-5373. ; 12:3-4, s. 195-201
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Journal article (peer-reviewed)abstract
- A set of moral problems known as The Trolley Dilemmas was presented to 3000 randomly selected inhabitants of the USA, Russia and China. It is shown that Chinese are significantly less prone to support utility-maximizing alternatives, as compared to the US and Russian respondents.A number of possible explanations, as well as methodological issues pertaining to the field of surveying moral judgment and moral disagreement, are discussed.
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| 4. |
- Ahlenius, Henrik, et al.
(author)
-
Isolation and generation of neurosphere cultures from embryonic and adult mouse brain.
- 2010
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In: Methods in Molecular Biology. - Totowa, NJ : Humana Press. - 1940-6029. ; 633, s. 241-252
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Journal article (peer-reviewed)abstract
- Neural stem cells are defined as cells that either gives rise to or derives from the cells of the central nervous system and have the unique properties of stem cells, i.e. self-renewal and multipotentiality. One of the widely used methods of expanding neural stem cells under culture conditions is based on the capacity of these cells to divide continuously when cultured in serum-free medium supplemented with various growth factors. One common method used is to grow neural stem cells as free-floating aggregates of cells called neurospheres. Neurospheres can be generated from several structures of the embryonic and adult mammalian brain. Although viable lines can be generated from crude extracts of brain, a precise dissection is crucial to get a pure population of cells. Here we describe methods for dissection, isolation and generation of neurospheres from embryonic ganglionic eminences and adult subventricular zone of mice and rats.
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| 5. |
- Ahlenius, Henrik, 1973-
(author)
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Moral Lessons from Psychology : Contemporary Themes in Psychological Research and their Relevance for Ethical Theory
- 2020
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Doctoral thesis (other academic/artistic)abstract
- The thesis investigates the implications for moral philosophy of research in psychology. In addition to an introduction and concluding remarks, the thesis consists of four chapters, each exploring various more specific challenges or inputs to moral philosophy from cognitive, social, personality, developmental, and evolutionary psychology. Chapter 1 explores and clarifies the issue of whether or not morality is innate. The chapter’s general conclusion is that evolution has equipped us with a basic suite of emotions that shape our moral judgments in important ways. Chapter 2 presents and investigates the challenge presented to deontological ethics by Joshua Greene’s so-called dual process theory. The chapter partly agrees with his conclusion that the dual process view neutralizes some common criticisms against utilitarianism founded on deontological intuitions, but also points to avenues left to explore for deontologists. Chapter 3 focuses on Katarzyna de Lazari-Radek and Peter Singer’s suggestion that utilitarianism is less vulnerable to so-called evolutionary debunking than other moral theories. The chapter is by and large critical of their attempt. In the final chapter 4, attention is directed at the issue of whether or not social psychology has shown that people lack stable character traits, and hence that the virtue ethical view is premised on false or tenuous assumptions. Though this so-called situationist challenge at one time seemed like a serious threat to virtue ethics, the chapter argues for a moderate position, pointing to the fragility of much of the empirical research invoked to substantiate this challenge while also suggesting revisions to the virtue ethical view as such.
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| 6. |
- Ahlenius, Henrik, et al.
(author)
-
Neural stem and progenitor cells retain their potential for proliferation and differentiation into functional neurons despite lower number in aged brain.
- 2009
-
In: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 29:14, s. 4408-4419
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Journal article (peer-reviewed)abstract
- Neurogenesis in the subventricular zone (SVZ), which gives rise to new neurons in the olfactory bulb, continues throughout life but declines with increasing age. Little is known about how aging affects the intrinsic properties of the neural stem and progenitor cells (NSCs) in SVZ and the functional characteristics of their neuronal progeny. Here, we have compared the properties of NSCs isolated from embryonic lateral ganglionic eminence and adult and aged SVZ in mice using in vivo and in vitro systems, analyzed their gene expression profile, and studied their electrophysiological characteristics before and after differentiation into neurons. We show a loss of NSCs in SVZ from aged mice accompanied by reduced expression of genes for NSC markers, developmentally important transcription factors, and neurogenic factors. However, when isolated in vitro, the NSCs from SVZ of aged animals have capacity for proliferation and multilineage differentiation, including production of functional neurons, similar to that of NSCs in adult mice, albeit with lower efficacy. These properties are of major importance when considering therapeutic applications of neuronal replacement from endogenous NSCs in the injured, aged brain.
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| 7. |
- Ahlenius, Henrik
(author)
-
Past, Present, and Future of Direct Cell Reprogramming
- 2022
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In: Cellular Reprogramming. - : Mary Ann Liebert Inc. - 2152-4971 .- 2152-4998. ; 24:5, s. 205-211
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Journal article (peer-reviewed)abstract
- Budding off from the broader developmental biology and stem cell research fields, cellular reprogramming is now established as a prominent discipline in its own right. Direct cell reprogramming is defined as the cell fate conversion of a somatic cell toward another identity without a pluripotent intermediate state. In addition to the opportunity for mechanistic dissection of lineage commitment in human cells, the field offer the promise of diverse applications such as for disease modeling, cell replacement therapy, regenerative medicine, and immunotherapy that have recently spurred innovation and out of the box thinking to unleash the potential of cellular plasticity.
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| 8. |
- Ahlenius, Henrik
(author)
-
Preface
- 2021
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In: Methods in Molecular Biology. - 1064-3745. ; 2352
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Journal article (other academic/artistic)
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| 9. |
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| 10. |
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| 11. |
- Benetó, Noelia, et al.
(author)
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Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development
- 2020
-
In: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 9:3
-
Journal article (peer-reviewed)abstract
- Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated new neuronal and astrocytic models of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients' fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocytic models of Sanfilippo syndrome for future studies on disease mechanisms and drug development.
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| 12. |
- Canals, Isaac, et al.
(author)
-
Astrocyte dysfunction and neuronal network hyperactivity in a CRISPR engineered pluripotent stem cell model of frontotemporal dementia
- 2023
-
In: Brain Communications. - 2632-1297. ; 5:3, s. 1-16
-
Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is the second most prevalent type of early-onset dementia and up to 40% of cases are familial forms. One of the genes mutated in patients is CHMP2B, which encodes a protein found in a complex important for maturation of late endosomes, an essential process for recycling membrane proteins through the endolysosomal system. Here, we have generated a CHMP2B-mutated human embryonic stem cell line using genome editing with the purpose to create a human in vitro FTD disease model. To date, most studies have focused on neuronal alterations; however, we present a new co-culture system in which neurons and astrocytes are independently generated from human embryonic stem cells and combined in co-cultures. With this approach, we have identified alterations in the endolysosomal system of FTD astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and a neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development.
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| 13. |
- Canals, Isaac, et al.
(author)
-
CRISPR/Cas9 Genome Engineering in Human Pluripotent Stem Cells for Modeling of Neurological Disorders
- 2021
-
In: Neural Reprogramming : Methods and Protocols - Methods and Protocols. - New York, NY : Springer US. - 1940-6029 .- 1064-3745. - 9781071616017 - 9781071616000 ; 2352, s. 237-251
-
Book chapter (peer-reviewed)abstract
- Recent advances in genome editing have brought new hopes for personalized and precision medicine but have also dramatically facilitated disease modeling studies. Combined with reprogramming approaches, stem cells and differentiation toward neural lineages, genome engineering holds great potential for regenerative approaches and to model neurological disorders. The use of patient-specific induced pluripotent stem cells combined with neural differentiation allows studying the effect of specific mutations in different brain cells. New genome editing tools such as CRISPR/Cas9 represent a step further by facilitating the introduction or correction of specific mutations within the same cell line, thus eliminating variability due to differences in the genetic background. Here, we present a step-by-step protocol from design to generation of human pluripotent stem cell lines with specific mutations introduced or corrected with CRISPR/Cas9 gene editing that can be used in combination with transcription factor-based protocols to dissect underlying mechanisms of neurological disorders.
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| 14. |
- Canals, Isaac, et al.
(author)
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Rapid and efficient induction of functional astrocytes from human pluripotent stem cells
- 2018
-
In: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 15:9, s. 693-696
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Journal article (peer-reviewed)abstract
- The derivation of astrocytes from human pluripotent stem cells is currently slow and inefficient. We demonstrate that overexpression of the transcription factors SOX9 and NFIB in human pluripotent stem cells rapidly and efficiently yields homogeneous populations of induced astrocytes. In our study these cells exhibited molecular and functional properties resembling those of adult human astrocytes and were deemed suitable for disease modeling. Our method provides new possibilities for the study of human astrocytes in health and disease.
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| 15. |
- Canals, Isaac, et al.
(author)
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Transcription Factor-Based Strategies to Generate Neural Cell Types from Human Pluripotent Stem Cells
- 2021
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In: Cellular Reprogramming. - : Mary Ann Liebert Inc. - 2152-4971 .- 2152-4998. ; 23:4, s. 206-220
-
Research review (peer-reviewed)abstract
- In the last years, the use of pluripotent stem cells in studies of human biology has grown exponentially. These cells represent an infinite source for differentiation into several human cell types facilitating the investigation on biological processes, functionality of cells, or diseases mechanisms in relevant human models. In the neurobiology field, pluripotent stem cells have been extensively used to generate the main neuronal and glial cells of the brain. Traditionally, protocols following developmental cues have been applied to pluripotent stem cells to drive differentiation toward different cell lineages; however, these protocols give rise to populations with mixed identities. Interestingly, new protocols applying overexpression of lineage-specific transcription factors (TFs) have emerged and facilitated the generation of highly pure populations of specific subtypes of neurons and glial cells in an easy, reproducible, and rapid manner. In this study, we review protocols based on this strategy to generate excitatory, inhibitory, dopaminergic, and motor neurons as well as astrocytes, oligodendrocytes, and microglia. In addition, we will discuss the main applications for cells generated with these protocols, including disease modeling, drug screening, and mechanistic studies. Finally, we will discuss the advantages and disadvantages of TF-based protocols and present our view of the future in this field.
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| 16. |
- Chanoumidou, Konstantina, et al.
(author)
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Groucho related gene 5 (GRG5) is involved in embryonic and neural stem cell state decisions
- 2018
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
-
Journal article (peer-reviewed)abstract
- Groucho related gene 5 (GRG5) is a multifunctional protein that has been implicated in late embryonic and postnatal mouse development. Here, we describe a previously unknown role of GRG5 in early developmental stages by analyzing its function in stem cell fate decisions. By both loss and gain of function approaches we demonstrate that ablation of GRG5 deregulates the Embryonic Stem Cell (ESC) pluripotent state whereas its overexpression leads to enhanced self-renewal and acquisition of cancer cell-like properties. The malignant characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its pro-oncogenic potential. Furthermore, transcriptomic analysis and cell differentiation approaches underline GRG5 as a multifaceted signaling regulator that represses mesendodermal-related genes. When ESCs exit pluripotency, GRG5 promotes neuroectodermal specification via Wnt and BMP signaling suppression. Moreover, GRG5 promotes the neuronal reprogramming of fibroblasts and maintains the self-renewal of Neural Stem Cells (NSCs) by sustaining the activity of Notch/Hes and Stat3 signaling pathways. In summary, our results demonstrate that GRG5 has pleiotropic roles in stem cell biology functioning as a stemness factor and a neural fate specifier.
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| 17. |
- Chapman, Katie, et al.
(author)
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Inflammation without neuronal death triggers striatal neurogenesis comparable to stroke.
- 2015
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 83:Aug 20, s. 1-15
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Journal article (peer-reviewed)abstract
- Ischemic stroke triggers neurogenesis from neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ) and migration of newly formed neuroblasts towards the damaged striatum where they differentiate to mature neurons. Whether it is the injury per se or the associated inflammation that gives rise to this endogenous neurogenic response is unknown. Here we showed that inflammation without corresponding neuronal loss caused by intrastriatal lipopolysaccharide (LPS) injection leads to striatal neurogenesis in rats comparable to that after a 30min middle cerebral artery occlusion, as characterized by striatal DCX+ neuroblast recruitment and mature NeuN+/BrdU+ neuron formation. Using global gene expression analysis, changes in several factors that could potentially regulate striatal neurogenesis were identified in microglia sorted from SVZ and striatum of LPS-injected and stroke-subjected rats. Among the upregulated factors, one chemokine, CXCL13, was found to promote neuroblast migration from neonatal mouse SVZ explants in vitro. However, neuroblast migration to the striatum was not affected in constitutive CXCL13 receptor CXCR5(-/-) mice subjected to stroke. Infarct volume and pro-inflammatory M1 microglia/macrophage density were increased in CXCR5(-/-) mice, suggesting that microglia-derived CXCL13, acting through CXCR5, might be involved in neuroprotection following stroke. Our findings raise the possibility that the inflammation accompanying an ischemic insult is the major inducer of striatal neurogenesis after stroke.
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| 18. |
- Cusulin, Carlo, et al.
(author)
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Embryonic Stem Cell-Derived Neural Stem Cells Fuse with Microglia and Mature Neurons.
- 2012
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In: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099.
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Journal article (peer-reviewed)abstract
- Transplantation of neural stem cells (NSCs) is a novel strategy to restore function in the diseased brain, acting through multiple mechanisms, e.g., neuronal replacement, neuroprotection and modulation of inflammation. Whether transplanted NSCs can operate by fusing with microglial cells or mature neurons is largely unknown. Here we have studied the interaction of a mouse embryonic stem cell-derived neural stem (NS) cell line with rat and mouse microglia and neurons in vitro and in vivo. We show that NS cells spontaneously fuse with co-cultured cortical neurons, and that this process requires the presence of microglia. Our in vitro data indicate that the NS cells can first fuse with microglia, and then with neurons. The fused NS/microglial cells express markers and retain genetic and functional characteristics of both parental cell types, being able to respond to microglia-specific stimuli (LPS and IL-4/IL-13) and to differentiate to neurons and astrocytes. The NS cells fuse with microglia, at least partly, through interaction between phosphatidylserine (PS) exposed on the surface of NS cells and CD36 receptor on microglia. Transplantation of NS cells into rodent cortex results in fusion with mature pyramidal neurons, which often carry two nuclei, a process probably mediated by microglia. The fusogenic role of microglia could be even more important after NSC transplantation into brains affected by neurodegenerative diseases associated with microglia activation. It remains to be elucidated how the occurrence of the fused cells will influence the functional outcome after NSC transplantation in the diseased brain.
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| 19. |
- Danilov, Alexandre, et al.
(author)
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Ultrastructural and antigenic properties of neural stem cells and their progeny in adult rat subventricular zone.
- 2009
-
In: GLIA. - : Wiley. - 1098-1136 .- 0894-1491. ; Aug 15, s. 136-152
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Journal article (peer-reviewed)abstract
- Neural stem cells (NSCs) in the subventricular zone (SVZ) continuously generate olfactory bulb interneurons in the adult rodent brain. Based on their ultrastructural and antigenic properties, NSCs, transient amplifying precursor cells, and neuroblasts (B, C, and A cells, respectively) have been distinguished in mouse SVZ. Here, we aimed to identify these cell types in rat SVZ ultrastructurally and at the light microscopy level, and to determine the antigenic properties of each cell type using gold and fluorescence immunolabeling. We found astrocytes with single cilia (NSCs, correspond to B cells) and neuroblasts (A cells). We also observed mitotic cells, ependymal cells, displaced ependymal cells, and mature astrocytes. In contrast, transient amplifying precursor cells (C cells) were not detected. The NSCs and neuroblasts had epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor alpha (PDGFRalpha) expressed on the ciliary apparatus and were the only cell types incorporating the proliferation marker BrdU. Throughout mitosis, EGFR and PDGFRalpha were associated with the microtubule of the mitotic spindle. Ependymal and displaced ependymal cells also expressed EGFR and PDGFRalpha on their cilia but did not incorporate BrdU. Our findings indicate that the NSCs in adult rat SVZ give rise directly to neuroblasts. During mitosis, the NSCs disassemble the primary cilium and symmetrically distribute EGFR and PDGFRalpha among their progeny. (c) 2008 Wiley-Liss, Inc.
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| 20. |
- Fritze, Jonas, et al.
(author)
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Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain
- 2020
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In: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 38:9, s. 1175-1187
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Journal article (peer-reviewed)abstract
- Neurogenesis, the production of new neurons from neural stem cells, dramatically decreases during aging concomitantly with increased inflammation both systemically and in the brain. However, the precise role of inflammation and whether local or systemic factors drive the neurogenic decline during aging is poorly understood. Here, we identify CXCR5/5/CXCL13 signaling as a novel regulator of neurogenesis in the aged brain. The chemokine Cxcl13 was found to be upregulated in the brain during aging. Loss of its receptor, Cxcr5, led to increased proliferation and decreased numbers of neuroblasts in the aged subventricular zone (SVZ), together with accumulation of neuroblasts in the rostral migratory stream and olfactory bulb (OB), without increasing the amount of new mature neurons in the OB. The effect on proliferation and migration was specific to neuroblasts and likely mediated through increased levels of systemic IL-6 and local Cxcl12 expression in the SVZ. Our study raises the possibility of a new mechanism by which interplay between systemic and local alterations in inflammation regulates neurogenesis during aging.
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| 21. |
- Galera-Monge, Teresa, et al.
(author)
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Mitochondrial dysfunction and calcium dysregulation in leigh syndrome induced pluripotent stem cell derived neurons
- 2020
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 21:9
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Journal article (peer-reviewed)abstract
- Leigh syndrome (LS) is the most frequent infantile mitochondrial disorder (MD) and is characterized by neurodegeneration and astrogliosis in the basal ganglia or the brain stem. At present, there is no cure or treatment for this disease, partly due to scarcity of LS models. Current models generally fail to recapitulate important traits of the disease. Therefore, there is an urgent need to develop new human in vitro models. Establishment of induced pluripotent stem cells (iPSCs) followed by differentiation into neurons is a powerful tool to obtain an in vitro model for LS. Here, we describe the generation and characterization of iPSCs, neural stem cells (NSCs) and iPSC-derived neurons harboring the mtDNA mutation m.13513G>A in heteroplasmy. We have performed mitochondrial characterization, analysis of electrophysiological properties and calcium imaging of LS neurons. Here, we show a clearly compromised oxidative phosphorylation (OXPHOS) function in LS patient neurons. This is also the first report of electrophysiological studies performed on iPSC-derived neurons harboring an mtDNA mutation, which revealed that, in spite of having identical electrical properties, diseased neurons manifested mitochondrial dysfunction together with a diminished calcium buffering capacity. This could lead to an overload of cytoplasmic calcium concentration and the consequent cell death observed in patients. Importantly, our results highlight the importance of calcium homeostasis in LS pathology.
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| 22. |
- Ganic, Elvira, et al.
(author)
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MafA-Controlled Nicotinic Receptor Expression Is Essential for Insulin Secretion and Is Impaired in Patients with Type 2 Diabetes.
- 2016
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 14:8, s. 1991-2002
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Journal article (peer-reviewed)abstract
- Monoamine and acetylcholine neurotransmitters from the autonomic nervous system (ANS) regulate insulin secretion in pancreatic islets. The molecular mechanisms controlling neurotransmitter signaling in islet β cells and their impact on diabetes development are only partially understood. Using a glucose-intolerant, MafA-deficient mouse model, we demonstrate that MAFA controls ANS-mediated insulin secretion by activating the transcription of nicotinic (ChrnB2 and ChrnB4) and adrenergic (Adra2A) receptor genes, which are integral parts of acetylcholine- and monoamine-signaling pathways. We show that acetylcholine-mediated insulin secretion requires nicotinic signaling and that nicotinic receptor expression is positively correlated with insulin secretion and glycemic control in human donor islets. Moreover, polymorphisms spanning MAFA-binding regions within the human CHRNB4 gene are associated with type 2 diabetes. Our data show that MAFA transcriptional activity is required for establishing β cell sensitivity to neurotransmitter signaling and identify nicotinic signaling as a modulator of insulin secretion impaired in type 2 diabetes.
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| 23. |
- Gioia, Roberta, et al.
(author)
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Adult hippocampal neurogenesis and social behavioural deficits in the R451C Neuroligin3 mouse model of autism are reverted by the antidepressant fluoxetine
- 2023
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 165:3, s. 318-333
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Journal article (peer-reviewed)abstract
- Neuron generation persists throughout life in the hippocampus but is altered in animal models of neurological and neuropsychiatric diseases, suggesting that disease-associated decline in cognitive and emotional hippocampal-dependent behaviours might be functionally linked with dysregulation of postnatal neurogenesis. Depletion of the adult neural stem/progenitor cell (NSPCs) pool and neurogenic decline have been recently described in mice expressing synaptic susceptibility genes associated with autism spectrum disorder (ASDs). To gain further insight into mechanisms regulating neurogenesis in mice carrying mutations in synaptic genes related to monogenic ASDs, we used the R451C Neuroligin3 knock-in (Nlgn3 KI) mouse, which is characterized by structural brain abnormalities, deficits in synaptic functions and reduced sociability. We show that the number of adult-born neurons, but not the size of the NSPC pool, was reduced in the ventral dentate gyrus in knock-in mice. Notably, this neurogenic decline was rescued by daily injecting mice with 10 mg/Kg of the antidepressant fluoxetine for 20 consecutive days. Sustained treatment also improved KI mice's sociability and increased the number of c-Fos active adult-born neurons, compared with vehicle-injected KI mice. Our study uncovers neurogenesis-mediated alterations in the brain of R451C KI mouse, showing that the R451C Nlgn3 mutation leads to lasting, albeit pharmacologically reversible, changes in the brain, affecting neuron formation in the adult hippocampus. Our results suggest that fluoxetine can ameliorate social behaviour in KI mice, at least in part, by rescuing adult hippocampal neurogenesis, which may be relevant for the pharmacological treatment of ASDs. (Figure presented.).
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| 24. |
- Hansen, Marita Grønning, et al.
(author)
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In Vitro Functional Characterization of Human Neurons and Astrocytes Using Calcium Imaging and Electrophysiology
- 2019
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In: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer New York. - 1940-6029. ; 1919, s. 73-88
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Journal article (peer-reviewed)abstract
- Recent progress in stem cell biology and epigenetic reprogramming has opened up previously unimaginable possibilities to study and develop regenerative approaches for neurological disorders. Human neurons and glial cells can be generated by differentiation of embryonic and neural stem cells and from somatic cells through reprogramming to pluripotency (followed by differentiation) as well as by direct conversion. All of these cells have the potential to be used for studying and treating neurological disorders. However, before considering using human neural cells derived from these sources for modelling or regenerative purposes, they need to be verified in terms of functionality and similarity to endogenous cells in the central nervous system (CNS).In this chapter, we describe how to assess functionality of neurons and astrocytes derived from stem cells and through direct reprogramming, using calcium imaging and electrophysiology.
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| 25. |
- Iosif, Robert, et al.
(author)
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Suppression of stroke-induced progenitor proliferation in adult subventricular zone by tumor necrosis factor receptor 1.
- 2008
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 28, s. 1574-1587
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Journal article (peer-reviewed)abstract
- Stroke induced by middle cerebral artery occlusion leads to transiently increased progenitor proliferation in the subventricular zone (SVZ) and long-lasting striatal neurogenesis in adult rodents. Tumor necrosis factor-alpha (TNF-alpha) is upregulated in stroke-damaged brain. Whether TNF-alpha and its receptors influence SVZ progenitor proliferation after stroke is unclear. Here we show that the increased proliferation 1 week after stroke occurred concomitantly with elevated microglia numbers and TNF-alpha and TNF receptor-1 (TNF-R1) gene expression in the SVZ of wild-type mice. TNF receptor-1 was expressed on sorted SVZ progenitor cells from nestin-green fluorescent protein reporter mice. In animals lacking TNF-R1, stroke-induced SVZ cell proliferation and neuroblast formation were enhanced. In contrast, deletion of TNF-R1 did not alter basal or status epilepticus-stimulated cell proliferation in SVZ. Addition of TNF-alpha reduced the size and numbers of SVZ neurospheres through a TNF-R1-dependent mechanism without affecting cell survival. Our results provide the first evidence that TNF-R1 is a negative regulator of stroke-induced SVZ progenitor proliferation. Blockade of TNF-R1 signaling might be a novel strategy to promote the proliferative response in SVZ after stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 21 May 2008; doi:10.1038/jcbfm.2008.47.
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| 26. |
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| 27. |
- Kobayashi, Tohru, et al.
(author)
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Intracerebral Infusion of Glial Cell Line-Derived Neurotrophic Factor Promotes Striatal Neurogenesis After Stroke in Adult Rats.
- 2006
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In: Stroke: a journal of cerebral circulation. - 1524-4628. ; 37:9, s. 2361-2367
-
Journal article (peer-reviewed)abstract
- Background and Purpose-Stroke triggers increased progenitor proliferation in the subventricular zone (SVZ) and the generation of medium spiny neurons in the damaged striatum of rodents. We explored whether intrastriatal infusion of glial cell line-derived neurotrophic factor (GDNF) promotes neurogenesis after stroke. Methods-Adult rats were subjected to 2-hour middle cerebral artery occlusion (MCAO). GDNF was infused into the ischemic striatum either during the first week after MCAO, with the animals being killed directly thereafter, or during the third and fourth weeks, with the rats being killed 1 week later. New cells were labeled with 5'-bromo-2'deoxyuridine (BrdU) on day 7 or during the second week, respectively. Neurogenesis was assessed immunocytochemically with antibodies against BrdU and neuronal, glial, or progenitor markers. GDNF receptor expression was analyzed in SVZ tissue and neurospheres by reverse transcription-polymerase chain reaction and immunocytochemistry. Results-GDNF infusion increased cell proliferation in the ipsilateral SVZ and the recruitment of new neuroblasts into the striatum after MCAO and improved survival of new mature neurons. The GDNF receptor GFR alpha 1 was upregulated in the SVZ 1 week after MCAO and was coexpressed with markers of dividing progenitor cells. Conclusions-Intrastriatal infusion of GDNF in the postischernic period promotes several steps of striatal neurogenesis after stroke., partly through direct action on SVZ progenitors. Because delivery of GDNF has biological effects in the human brain, our data suggest that administration of this factor may promote neurciregenerative responses in stroke patients.
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| 28. |
- Mall, Moritz, et al.
(author)
-
Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates
- 2017
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 544:7649, s. 245-249
-
Journal article (peer-reviewed)abstract
- Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.
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| 29. |
- Miskinyte, Giedre, et al.
(author)
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Direct conversion of human fibroblasts to functional excitatory cortical neurons integrating into human neural networks
- 2017
-
In: Stem Cell Research and Therapy. - : Springer Science and Business Media LLC. - 1757-6512. ; 8:1
-
Journal article (peer-reviewed)abstract
- Background: Human fibroblasts can be directly converted to several subtypes of neurons, but cortical projection neurons have not been generated. Methods: Here we screened for transcription factor combinations that could potentially convert human fibroblasts to functional excitatory cortical neurons. The induced cortical (iCtx) cells were analyzed for cortical neuronal identity using immunocytochemistry, single-cell quantitative polymerase chain reaction (qPCR), electrophysiology, and their ability to integrate into human neural networks in vitro and ex vivo using electrophysiology and rabies virus tracing. Results: We show that a combination of three transcription factors, BRN2, MYT1L, and FEZF2, have the ability to directly convert human fibroblasts to functional excitatory cortical neurons. The conversion efficiency was increased to about 16% by treatment with small molecules and microRNAs. The iCtx cells exhibited electrophysiological properties of functional neurons, had pyramidal-like cell morphology, and expressed key cortical projection neuronal markers. Single-cell analysis of iCtx cells revealed a complex gene expression profile, a subpopulation of them displaying a molecular signature closely resembling that of human fetal primary cortical neurons. The iCtx cells received synaptic inputs from co-cultured human fetal primary cortical neurons, contained spines, and expressed the postsynaptic excitatory scaffold protein PSD95. When transplanted ex vivo to organotypic cultures of adult human cerebral cortex, the iCtx cells exhibited morphological and electrophysiological properties of mature neurons, integrated structurally into the cortical tissue, and received synaptic inputs from adult human neurons. Conclusions: Our findings indicate that functional excitatory cortical neurons, generated here for the first time by direct conversion of human somatic cells, have the capacity for synaptic integration into adult human cortex.
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| 30. |
- Miskinyte, Giedre, et al.
(author)
-
Transcription factor programming of human ES cells generates functional neurons expressing both upper and deep layer cortical markers
- 2018
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:10
-
Journal article (peer-reviewed)abstract
- Human neurodegenerative disorders affect specific types of cortical neurons. Efficient protocols for the generation of such neurons for cell replacement, disease modeling and drug screening are highly warranted. Current methods for the production of cortical neurons from human embryonic stem (ES) cells are often time-consuming and inefficient, and the functional properties of the generated cells have been incompletely characterized. Here we have used transcription factor (TF) programming with the aim to induce rapid differentiation of human ES cells to layer-specific cortical neurons (hES-iNs). Three different combinations of TFs, NEUROGENIN 2 (NGN2) only, NGN2 plus Forebrain Embryonic Zinc Finger-Like Protein 2 (FEZF2), and NGN2 plus Special AT-Rich Sequence-Binding Protein 2 (SATB2), were delivered to human ES cells by lentiviral vectors. We observed only subtle differences between the TF combinations, which all gave rise to the formation of pyramidal-shaped cells, morphologically resembling adult human cortical neurons expressing cortical projection neuron (PN) markers and with mature electrophysiological properties. Using ex vivo transplantation to human organotypic cultures, we found that the hES-iNs could integrate into adult human cortical networks. We obtained no evidence that the hES-iNs had acquired a distinct cortical layer phenotype. Instead, our single-cell data showed that the hES-iNs, similar to fetal human cortical neurons, expressed both upper and deep layer cortical neuronal markers. Taken together, our findings provide evidence that TF programming can direct human ES cells towards cortical neurons but that the generated cells are transcriptionally profiled to generate both upper and deep layer cortical neurons. Therefore, most likely additional cues will be needed if these cells should adopt a specific cortical layer and area identity.
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| 31. |
- Okenwa-Emegwa, Leah, 1973-, et al.
(author)
-
Dare to Ask! : A Model for Teaching Nursing Students about Identifying and Responding to Violence against Women and Domestic Violence
- 2024
-
In: Nursing Reports. - : MDPI. - 2039-439X .- 2039-4403. ; 14:1, s. 603-615
-
Journal article (peer-reviewed)abstract
- The role of nurses in identifying and responding to family violence and violence against women has long been established. However, nurses’ readiness to fully assume this role remains low due to various barriers and the sensitive nature of the subject. As part of capacity building to address this problem, an additional national qualitative learning target, i.e., to “show knowledge about men’s violence against women and violence in close relationships”, was introduced into the Swedish Higher Education Ordinance for nursing and seven other educational programs between 2017 and 2018. The aim of this paper is to describe how the national qualitative learning target is incorporated into the undergraduate nursing curriculum at the Swedish Red Cross University College. An overview of relevant teaching and learning activities and how they are organized is first presented, followed by the presentation of a proposed didactic model: Dare to Ask and Act! The model details a step-by-step progression from facts and figures, including the role of gender norms, to recognizing signs of abuse in complex clinical situations, as well as developing skills that enhance the courage to ask and act. Due to the sensitive nature of violence victimization, the proposed model reflects the importance of making the subject a reoccurring theme in undergraduate nursing education in order to boost nursing students’ interests and confidence to “Dare to Ask and Act!”. The model also shows that making the subject a recurring theme can be achieved with minimal disruptions to and without overcrowding an existing curriculum.
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| 32. |
- Okenwa-Emegwa, Leah, 1973-, et al.
(author)
-
Våga fråga och agera! : Undervisnings- och lärandeaktiviteter om mäns våld mot kvinnor och våld i nära relationer i sjuksköterskeprogrammet vid Röda Korsets Högskola
- 2021
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In: Socialmedicinsk Tidskrift. - Stockholm : Socialmedicinsk tidskrift. - 0037-833X. ; 98:4, s. 671-683
-
Journal article (peer-reviewed)abstract
- År 2017 infördes ett nytt nationellt examensmål ”visa kunskap om mäns våld mot kvinnor och våld i nära relationer” enligt SFS 2017: 857, i högskoleför-ordningen (SFS 1993:100) för vissa utbildningsprogram, där sjuksköterske-programmet är inkluderat. Syftet med denna artikel är att presentera hur det nationella examensmålet har implementerats i sjuksköterskeprogrammet vid Röda Korsets Högskola. Först ges en översikt avseende relevanta undervis-nings- och lärandeaktiviteter och hur de organiseras genom programmets utbildningsplan. I de avslutande reflektionerna presenteras den didaktiska Våga fråga och agera! -modellen. Modellen är en sammanfattning av Röda Korsets Högskolas tillvägagångssätt, det vill säga en stegvis progression i utbildningen från fakta, statistik, normer och värderingar, till att studenterna lär sig hur de kan upptäckta tecken på våld i komplexa kliniska situationer samt vikten av att ha mod att agera. Avslutningsvis är det vår uppfattning att ett tydligt upplägg är viktigt för att uppnå intentionerna med det nationella examensmålet, nämligen: Våga fråga och agera!
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| 33. |
- Oki, Koichi, et al.
(author)
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Human Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery After Grafting in Stroke-Damaged Brain.
- 2012
-
In: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 30:6, s. 1120-1133
-
Journal article (peer-reviewed)abstract
- Reprogramming of adult human somatic cells to induced pluripotent stem cells (iPSCs) is a novel approach to produce patient-specific cells for autologous transplantation. Whether such cells survive long-term, differentiate to functional neurons, and induce recovery in the stroke-injured brain is unclear. We have transplanted long-term self-renewing neuroepithelial-like stem (lt-NES) cells, generated from adult human fibroblast-derived iPSCs, into the stroke-damaged mouse and rat striatum or cortex. Recovery of forepaw movements was observed already at 1 week after transplantation. Improvement was most likely not due to neuronal replacement but was associated with increased vascular endothelial growth factor levels, probably enhancing endogenous plasticity. Transplanted cells stopped proliferating, could survive without forming tumors for at least 4 months, and differentiated to morphologically mature neurons of different subtypes. Neurons in intrastriatal grafts sent axonal projections to the globus pallidus. Grafted cells exhibited electrophysiological properties of mature neurons and received synaptic input from host neurons. Our study provides the first evidence that transplantation of human iPSC-derived cells is a safe and efficient approach to promote recovery after stroke and can be used to supply the injured brain with new neurons for replacement.
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| 34. |
- Popa-Wagner, Aurel, et al.
(author)
-
Neurobiology of Postischemic Recuperation in the Aged Mammalian Brain
- 2010
-
In: Neurovascular Medicine : Pursuing Cellular Longevity for Healthy Aging - Pursuing Cellular Longevity for Healthy Aging. - : Oxford University PressNew York. - 9780195326697 - 9780199864874
-
Book chapter (peer-reviewed)abstract
- Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are not well understood. Potential mechanism underlying functional recovery after brain ischemia in aged subjects include neuroinflammation, changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Studies suggest that behaviorally, aged rats were more severely impaired by ischemia than were young rats and showed diminished functional recovery. Both in old and young rats, the early intense proliferative activity following stroke leads to a precipitous formation of growthinhibiting scar tissue, a phenomenon amplified by the persistent expression of neurotoxic factors. Recent evidence shows that the human brain can respond to stroke with increased progenitor proliferation in aged patients, opening the possibilities of utilizing this intrinsic attempt for neuroregeneration of the human brain as a potential therapy for ischemic stroke.
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| 35. |
- Quist, Ella, et al.
(author)
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Transcription factor-based direct conversion of human fibroblasts to functional astrocytes
- 2022
-
In: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:7, s. 1620-1635
-
Journal article (peer-reviewed)abstract
- Astrocytes are emerging key players in neurological disorders. However, their role in disease etiology is poorly understood owing to inaccessibility of primary human astrocytes. Pluripotent stem cell-derived cells fail to mimic age and due to their clonal origin do not mimic genetic heterogeneity of patients. In contrast, direct conversion constitutes an attractive approach to generate human astrocytes that capture age and genetic diversity. We describe efficient direct conversion of human fibroblasts to functional induced astrocytes (iAs). Expression of the minimal combination Sox9 and Nfib generates iAs with molecular, phenotypic, and functional properties resembling primary human astrocytes. iAs could be obtained by conversion of fibroblasts covering the entire human lifespan. Importantly, iAs supported function of induced neurons obtained through direct conversion from the same fibroblast population. Fibroblast-derived iAs will become a useful tool to elucidate the biology of astrocytes and complement current in vitro models for studies of late-onset neurological disorders.
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| 36. |
- Quist, Ella, et al.
(author)
-
Transcription Factor Programming of Human Pluripotent Stem Cells to Functionally Mature Astrocytes for Monocultures and Cocultures with Neurons
- 2021
-
In: Neural Reprogramming: Methods and Protocols. - New York, NY : Springer US. - 1940-6029 .- 1064-3745. - 9781071616017 - 9781071616000 ; 2352, s. 133-148
-
Book chapter (peer-reviewed)abstract
- Astrocytes are essential cells for normal brain functionality and have recently emerged as key players in many neurological diseases. However, the limited availability of human primary astrocytes for cell culture studies hinders our understanding of their physiology and precise role in disease development and progression. Here, we describe a detailed step-by-step protocol to rapidly and efficiently generate functionally mature induced astrocytes (iAs) from human embryonic and induced pluripotent stem cells (hES/iPSCs). Astrocyte induction is accomplished by ectopic lentiviral expression of two gliogenic transcription factors, Sox9 and Nfib. iAs exhibit morphology features as well as gene and protein expression similar to human mature astrocytes and display important astrocytic functions, such as glutamate uptake, propagation of calcium waves, expression of various cytokines after stimulation, and support of synapse formation and function, making them suitable models for studying the role of astrocytes in health and disease. Moreover, we describe a procedure for cryopreservation of iAs for long-term storage or shipping. Finally, we provide the required information needed to set up cocultures with human induced neurons (iNs, also described in this book), generated from hES/iPSCs, to generate cocultures, allowing studies on astrocyte-neuron interactions and providing new insights in astrocyte-associated disease mechanisms.
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| 37. |
- Rossi, Derrick J, et al.
(author)
-
Cell intrinsic alterations underlie hematopoietic stem cell aging
- 2005
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 102:26, s. 9194-9199
-
Journal article (peer-reviewed)abstract
- Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.
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| 38. |
- Sitnicka Quinn, Ewa, et al.
(author)
-
Complementary Signaling through flt3 and Interleukin-7 Receptor {alpha} Is Indispensable for Fetal and Adult B Cell Genesis.
- 2003
-
In: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 198:10, s. 1495-1506
-
Journal article (peer-reviewed)abstract
- Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7R{alpha}, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7R{alpha} and FL completely lack visible LNs, conventional IgM+ B cells, IgA+ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL-/- x IL-7R{alpha}-/- BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7R{alpha}-/- mice, FL-/- x IL-7R{alpha}-/- mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7R{alpha} are indispensable for fetal and adult B cell development.
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| 39. |
- Sitnicka Quinn, Ewa, et al.
(author)
-
Critical role of FLT3 ligand in IL-7 receptor-independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors
- 2007
-
In: Blood. - Washington, DC : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 110:8, s. 2955-2964
-
Journal article (peer-reviewed)abstract
- The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow (BM) stem/progenitor cells that continuously replace thymic progenitors remain largely unknown. Herein, we show that fms-like tyrosine kinase 3 (Flt3) ligand (Fl)-deficient mice have distinct reductions in the earliest thymic progenitors in fetal, postnatal, and adult thymus. A critical role of FL in thymopoiesis was particularly evident in the absence of interleukin-7 receptor alpha (IL-7Ralpha) signaling. Fl-/-Il-7r-/- mice have extensive reductions in fetal and postnatal thymic progenitors that result in a loss of active thymopoiesis in adult mice, demonstrating an indispensable role of FL in IL-7Ralpha-independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Ralpha, in regulation of the earliest lineage-negative (Lin(-)) Lin(-)SCA1+KIT+ (LSK) FLT3(hi) lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.
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| 40. |
- Thored, Per, et al.
(author)
-
Persistent production of neurons from adult brain stem cells during recovery after stroke.
- 2006
-
In: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 24:3, s. 739-747
-
Journal article (peer-reviewed)abstract
- Neural stem cells in the subventricular zone of adult rodents produce new striatal neurons that may replace those that have died after stroke; however, the neurogenic response has been considered acute and transient, yielding only small numbers of neurons. In contrast, we show herein that striatal neuroblasts are generated without decline at least for 4 months after stroke in adult rats. Neuroblasts formed early or late after stroke either differentiate into mature neurons, which survive for several months, or die through caspase-mediated apoptosis. The directed migration of the new neurons toward the ischemic damage is regulated by stromal cell-derived factor-la and its receptor CXCR4. These results show that endogenous neural stem cells continuously supply the injured adult brain with new neurons, which suggests novel self-repair strategies to improve recovery after stroke.
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| 41. |
- Trovato, Francesco, et al.
(author)
-
Transcription Factor-Forced Astrocytic Differentiation Impairs Human Glioblastoma Growth In Vitro and In Vivo
- 2023
-
In: Molecular Cancer Therapeutics. - 1538-8514. ; 22:2, s. 274-286
-
Journal article (peer-reviewed)abstract
- Direct cellular reprogramming has recently gained attention of cancer researchers for the possibility to convert undifferentiated cancer cells into more differentiated, postmitotic cell types. While a few studies have attempted reprogramming of glioblastoma (GBM) cells toward a neuronal fate, this approach has not yet been used to induce differentiation into other lineages and in vivo data on reduction in tumorigenicity are limited. Here, we employ cellular reprogramming to induce astrocytic differentiation as a therapeutic approach in GBM. To this end, we overexpressed key transcriptional regulators of astroglial development in human GBM and GBM stem cell lines. Treated cells undergo a remarkable shift in structure, acquiring an astrocyte-like morphology with star-shaped bodies and radial branched processes. Differentiated cells express typical glial markers and show a marked decrease in their proliferative state. In addition, forced differentiation induces astrocytic functions such as induced calcium transients and ability to respond to inflammatory stimuli. Most importantly, forced differentiation substantially reduces tumorigenicity of GBM cells in an in vivo xenotransplantation model. The current study capitalizes on cellular plasticity with a novel application in cancer. We take advantage of the similarity between neural developmental processes and cancer hierarchy to mitigate, if not completely abolish, the malignant nature of tumor cells and pave the way for new intervention strategies.
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| 42. |
- Warnling Conradson, Wiweka, et al.
(author)
-
Lärare & elev : rättsliga aspekter och etiska dilemman
- 2018. - 2
-
Book (other academic/artistic)abstract
- Denna bok inom det skoljuridiska området fokuserar på mötet mellan lärare och elev och vilka rättsliga aspekter, ofta förknippade med etiska dilemman, som detta kan aktualisera. Tanken är att lära sig se dessa aspekter och dilemman i vardagliga situationer för att på så sätt kunna parera ett antal s.k. blindskär i yrkesrollen som lärare.
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| 43. |
- Wattananit, Somsak, et al.
(author)
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Monocyte-derived macrophages contribute to spontaneous long-term functional recovery after stroke in mice
- 2016
-
In: The Journal of Neuroscience. - 0270-6474. ; 36:15, s. 4182-4195
-
Journal article (peer-reviewed)abstract
- Stroke is a leading cause of disability and currently lacks effective therapy enabling long-term functional recovery. Ischemic brain injury causes local inflammation, which involves both activated resident microglia and infiltrating immune cells, including monocytes. Monocyte-derived macrophages (MDMs) exhibit a high degree of functional plasticity. Here, we determined the role of MDMs in longterm spontaneous functional recovery after middle cerebral artery occlusion in mice. Analyses by flow cytometry and immunocytochemistry revealed that monocytes home to the stroke-injured hemisphere., and that infiltration peaks 3 d after stroke. At day 7, half of the infiltratingMDMsexhibited a bias toward a proinflammatory phenotype and the other half toward an anti-inflammatory phenotype, but during the subsequent 2 weeks, MDMs with an anti-inflammatory phenotype dominated. Blocking monocyte recruitment using the anti-CCR2 antibody MC-21 during the first week after stroke abolished long-term behavioral recovery, as determined in corridor and staircase tests, and drastically decreased tissue expression of anti-inflammatory genes, including TGFβ, CD163, and Ym1. Our results show that spontaneously recruited monocytes to the injured brain early after the insult contribute to long-term functional recovery after stroke.
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