1.
Pfisterer, Ulrich, et al.
(author)
Direct conversion of human fibroblasts to dopaminergic neurons.
2011
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 108:25, s. 10343-10348
Journal article (peer-reviewed) abstract
Recent reports demonstrate that somatic mouse cells can be directly converted to other mature cell types by using combined expression of defined factors. Here we show that the same strategy can be applied to human embryonic and postnatal fibroblasts. By overexpression of the transcription factors Ascl1, Brn2, and Myt1l, human fibroblasts were efficiently converted to functional neurons. We also demonstrate that the converted neurons can be directed toward distinct functional neurotransmitter phenotypes when the appropriate transcriptional cues are provided together with the three conversion factors. By combining expression of the three conversion factors with expression of two genes involved in dopamine neuron generation, Lmx1a and FoxA2, we could direct the phenotype of the converted cells toward dopaminergic neurons. Such subtype-specific induced neurons derived from human somatic cells could be valuable for disease modeling and cell replacement therapy.
2.
Kokaia, Zaal, et al.
(author)
Sensors of Succinate : Neural Stem Cell Grafts Fight Neuroinflammation
2018
In: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 22:3, s. 283-285
Journal article (peer-reviewed) abstract
In this issue of Cell Stem Cell, Peruzzotti-Jametti et al. (2018) demonstrate how neural stem cells, transplanted in a mouse model of multiple sclerosis, respond to extracellular succinate and modulate neuroinflammation by releasing anti-inflammatory prostaglandin E2 and scavenging succinate. This mechanism reduces CNS damage and ameliorates motor impairment. In this issue of Cell Stem Cell, Peruzzotti-Jametti et al. (2018) demonstrate how neural stem cells, transplanted in a mouse model of multiple sclerosis, respond to extracellular succinate and modulate neuroinflammation by releasing anti-inflammatory prostaglandin E2 and scavenging succinate. This mechanism reduces CNS damage and ameliorates motor impairment.
3.
Lindvall, Olle, et al.
(author)
Stem cells for the treatment of neurological disorders.
2006
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 441:7097, s. 1094-1096
Journal article (peer-reviewed) abstract
Many common neurological disorders, such as Parkinson's disease, stroke and multiple sclerosis, are caused by a loss of neurons and glial cells. In recent years, neurons and glia have been generated successfully from stem cells in culture, fuelling efforts to develop stem-cell-based transplantation therapies for human patients. More recently, efforts have been extended to stimulating the formation and preventing the death of neurons and glial cells produced by endogenous stem cells within the adult central nervous system. The next step is to translate these exciting advances from the laboratory into clinically useful therapies.
4.
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.
5.
Santopolo, Giuseppe, et al.
(author)
Blocking Notch-Signaling Increases Neurogenesis in the Striatum after Stroke
2020
In: Cells. - : MDPI AG. - 2073-4409. ; 9:7
Journal article (peer-reviewed) abstract
Stroke triggers neurogenesis in the striatum in mice, with new neurons deriving in part from the nearby subventricular zone and in part from parenchymal astrocytes. The initiation of neurogenesis by astrocytes within the striatum is triggered by reduced Notch-signaling, and blocking this signaling pathway by deletion of the gene encoding the obligate Notch coactivator Rbpj is sufficient to activate neurogenesis by striatal astrocytes in the absence of an injury. Here we report that blocking Notch-signaling in stroke increases the neurogenic response to stroke 3.5-fold in mice. Deletion of Rbpj results in the recruitment of a larger number of parenchymal astrocytes to neurogenesis and over larger areas of the striatum. These data suggest inhibition of Notch-signaling as a potential translational strategy to promote neuronal regeneration after stroke.
6.
Ahlenius, Henrik, et al.
(author)
Adaptor Protein LNK Is a Negative Regulator of Brain Neural Stem Cell Proliferation after Stroke.
2012
In: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:15, s. 5151-5164
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.
7.
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
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.
8.
9.
Ajmone-Cat, Maria Antonietta, et al.
(author)
Prostaglandin E(2) and BDNF levels in rat hippocampus are negatively correlated with status epilepticus severity: No impact on survival of seizure-generated neurons.
2006
In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 23:1, s. 23-35
Journal article (peer-reviewed) abstract
Partial and generalized status epilepticus (pSE and gSE) trigger the same level of progenitor cell proliferation in adult dentate gyrus, but survival of new neurons is poor after gSE. Here, we show markedly elevated levels of prostaglandin E-2 (PGE(2)) and brain-derived neurotrophic factor (BDNF) in rat hippocampal formation at 7 days following pSE but not gSE. Administration of the cyclooxygenase (COX) inhibitor flurbiprofen for 1 week, starting at day 8 post-SE, abated PGE(2) and decreased BDNF levels, but did not affect survival of new neurons a weeks later. Thus, high PGE(2) and BDNF levels induced by pSE are probably not of major importance for survival of new neurons during the first days after formation. We propose that they modulate other aspects of synaptic and cellular plasticity, and thereby may influence epileptogenesis.
10.
Andsberg, Gunnar, et al.
(author)
Neuropathological and behavioral consequences of adeno-associated viral vector-mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats.
2002
In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 9:2, s. 187-204
Journal article (peer-reviewed) abstract
Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were continuously delivered to the striatum at biologically active levels via recombinant adeno-associated viral (rAAV) gene transfer 4-5 weeks prior to 30 min of middle cerebral artery occlusion (MCAO). The magnitude of the deficits in a battery of behavioral tests designed to assess striatal function was highly correlated to the extent of ischemic damage determined by unbiased stereological estimations of striatal neuron numbers. The delivery of neurotrophins lead to mild functional improvements in the ischemia-induced motor impairments assessed 3-5 weeks after the insult, in agreement with a small but significant increase of the survival of dorsolateral striatal neurons. Detailed phenotypic analysis demonstrated that the parvalbumin-containing interneurons were spared to a greater extent by the neurotrophin treatment as compared to the projection neurons, which agreed with the specificity for interneuron transduction by the rAAV vector. These data show the advantage of the never previously performed combination of precise quantification of the ischemia-induced neuropathology along with detailed behavioural analysis for assessing neuroprotection after stroke. We observe that intrastriatal delivery of NGF and BDNF using a viral vector system can mitigate, albeit only moderately, neuronal death following stroke, which leads to detectable functional sparing. (c)2002 Elsevier Science (USA).
