696 research outputs found
The Use of Human Samples to Study Familial and Sporadic Amyotrophic Lateral Sclerosis: New Frontiers and Challenges
IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes
Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage
Extreme Low Light Requirement for Algae Growth Underneath Sea Ice:A Case Study From Station Nord, NE Greenland
Microalgae colonizing the underside of sea ice in spring are a key component of the Arctic foodweb as they drive early primary production and transport of carbon from the atmosphere to the ocean interior. Onset of the spring bloom of ice algae is typically limited by the availability of light, and the current consensus is that a few tensâofâcentimeters of snow is enough to prevent sufficient solar radiation to reach underneath the sea ice. We challenge this consensus, and investigated the onset and the light requirement of an ice algae spring bloom, and the importance of snow optical properties for light penetration. Colonization by ice algae began in May under >1 m of firstâyear sea ice with âŒ1 m thick snow cover on top, in NE Greenland. The initial growth of ice algae began at extremely low irradiance (<0.17 ÎŒmol photons mâ2 sâ1) and was documented as an increase in Chlorophyll a concentration, an increase in algal cell number, and a viable photosynthetic activity. Snow thickness changed little during May (from 110 to 91 cm), however the snow temperature increased steadily, as observed from automated highâfrequency temperature profiles. We propose that changes in snow optical properties, caused by temperatureâdriven snow metamorphosis, was the primary driver for allowing sufficient light to penetrate through the thick snow and initiate algae growth below the sea ice. This was supported by radiativeâtransfer modeling of light attenuation. Implications are an earlier productivity by ice algae in Arctic sea ice than recognized previously
Potent spinal parenchymal AAV9-mediated gene delivery by subpial injection in adult rats and pigs.
Effective in vivo use of adeno-associated virus (AAV)-based vectors to achieve gene-specific silencing or upregulation in the central nervous system has been limited by the inability to provide more than limited deep parenchymal expression in adult animals using delivery routes with the most clinical relevance (intravenous or intrathecal). Here, we demonstrate that the spinal pia membrane represents the primary barrier limiting effective AAV9 penetration into the spinal parenchyma after intrathecal AAV9 delivery. We develop a novel subpial AAV9 delivery technique and AAV9-dextran formulation. We use these in adult rats and pigs to show (i) potent spinal parenchymal transgene expression in white and gray matter including neurons, glial and endothelial cells after single bolus subpial AAV9 delivery; (ii) delivery to almost all apparent descending motor axons throughout the length of the spinal cord after cervical or thoracic subpial AAV9 injection; (iii) potent retrograde transgene expression in brain motor centers (motor cortex and brain stem); and (iv) the relative safety of this approach by defining normal neurological function for up to 6 months after AAV9 delivery. Thus, subpial delivery of AAV9 enables gene-based therapies with a wide range of potential experimental and clinical utilizations in adult animals and human patients
An NF-ÎșB - EphrinA5-Dependent Communication between NG2+ Interstitial Cells and Myoblasts Promotes Muscle Growth in Neonates
SummarySkeletal muscle growth immediately following birth is critical for proper body posture and locomotion. However, compared with embryogenesis and adulthood, the processes regulating the maturation of neonatal muscles is considerably less clear. Studies in the 1960s predicted that neonatal muscle growth results from nuclear accretion of myoblasts preferentially at the tips of myofibers. Remarkably, little information has been added since then to resolve how myoblasts migrate to the ends of fibers. Here, we provide insight into this process by revealing a unique NF-ÎșB-dependent communication between NG2+ interstitial cells and myoblasts. NF-ÎșB in NG2+ cells promotes myoblast migration to the tips of myofibers through cell-cell contact. This occurs through expression of ephrinA5 from NG2+ cells, which we further deduce is an NF-ÎșB target gene. Together, these results suggest that NF-ÎșB plays an important role in the development of newborn muscles to ensure proper myoblast migration for fiber growth
Strategies to develop a prophylaxis for the prevention of HPA-1a immunization and fetal and neonatal alloimmune thrombocytopenia
Oligodendrocytes contribute to motor neuron death in ALS via SOD1 dependent mechanism
Oligodendrocytes have recently been implicated in the pathophysiology of ALS. Here we show that, in vitro, mutant SOD1 mouse oligodendrocytes induce wild-type motor neuron hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls, sporadic and familial ALS patients using two different reprogramming methods. All ALS oligodendrocyte lines induced motor neuron death through conditioned medium and in co-culture. Conditioned medium-mediated motor neuron death was associated with decreased lactate production and release, while toxicity in co-culture was lactate independent, demonstrating that motor neuron survival is not only mediated by soluble factors.
Remarkably, human SOD1 shRNA treatment resulted in motor neuron rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, while it was ineffective in differentiated oligodendrocytes.
Early SOD1 knockdown, in fact, rescued lactate impairment and cell toxicity in all lines tested with exclusion of samples carrying C9orf72 repeat expansions. These did not respond to SOD1 knockdown nor showed lactate release impairment.
Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type some damage might be irreversible. In addition, we demonstrate that C9ORF72 patients represent an independent patient group that might not respond to the same treatment
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