What is the potential of oligodendrocyte progenitor cells to successfully treat human spinal cord injury?

<p>Abstract</p> <p>Background</p> <p>Spinal cord injury is a serious and debilitating condition, affecting millions of people worldwide. Long seen as a permanent injury, recent advances in stem cell research have brought closer the possibility of repairing the spinal cord. One such approach involves injecting oligodendrocyte progenitor cells, derived from human embryonic stem cells, into the injured spinal cord in the hope that they will initiate repair. A phase I clinical trial of this therapy was started in mid 2010 and is currently underway.</p> <p>Discussion</p> <p>The theory underlying this approach is that these myelinating progenitors will phenotypically replace myelin lost during injury whilst helping to promote a repair environment in the lesion. However, the importance of demyelination in the pathogenesis of human spinal cord injury is a contentious issue and a body of literature suggests that it is only a minor factor in the overall injury process.</p> <p>Summary</p> <p>This review examines the validity of the theory underpinning the on-going clinical trial as well as analysing published data from animal models and finally discussing issues surrounding safety and purity in order to assess the potential of this approach to successfully treat acute human spinal cord injury.</p

Retinoid X receptor gamma signaling accelerates CNS remyelination

The molecular basis of CNS myelin regeneration (remyelination) is poorly understood. We generated a comprehensive transcriptional profile of the separate stages of spontaneous remyelination that follow focal demyelination in the rat CNS and found that transcripts that encode the retinoid acid receptor RXR-γ were differentially expressed during remyelination. Cells of the oligodendrocyte lineage expressed RXR-γ in rat tissues that were undergoing remyelination and in active and remyelinated multiple sclerosis lesions. Knockdown of RXR-γ by RNA interference or RXR-specific antagonists severely inhibited oligodendrocyte differentiation in culture. In mice that lacked RXR-γ, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated cerebellar slice cultures and to aged rats after demyelination caused an increase in remyelinated axons. Our results indicate that RXR-γ is a positive regulator of endogenous oligodendrocyte precursor cell differentiation and remyelination and might be a pharmacological target for regenerative therapy in the CNS

Analysis of water resources in Safford, Arizona.

Safford Valley, Arizona obtains irrigation water from a combination of surface water and ground water. Sometimes during the summer both surface and ground water are not enough for crop demands. Ground water is very high in dissolved solids. Every year approximately 200,000 tons of dissolved solids are deposited on the crop lands in the irrigation water. The total annual irrigation water requirement in the valley, as estimated by the Blaney-Criddle method, is 241,000 acre-feet. Diverted water plus pumpage is 210,000 acre-ft. per year. Total net annual water use in the valley, as estimated by a water budget equation, is 107,000 acre-ft. Diverted plus pumped water less the net volume of water • represents water lost to seepage from the valley. Historical data records were used to generate data by a lag-one Markov process using statistical parameters from five different periods. The generated data were then used to estimate storage capacity of a proposed reservoir by flow-mass curve analysis. The 100-year flood was estimated by flood frquency analysis using three different frequency distributions. The extreme flood, as plotted on Gumbel, arithmetic and log-normal probability paper was found to be 78,000, 75,000 and 126,000 cubic feet per second (cfs), respectively. Three water management alternatives were suggested for the purpose of improving water use in the basin. The alternative that was more efficient in irrigation practices was recommended.hydrology collectio

Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS

Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell–derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies