Spinal cord injury (SCI) is a major cause of paralysis. Currently, there are no effective therapies to reverse this disabling condition. The presence of ependymal stem/progenitor cells (epSPCs) in the adult spinal cord suggests that endogenous stem cell-associated mechanisms might be exploited to repair spinal cord lesions. epSPC cells that proliferate after SCI are recruited by the injured zone, and can be modulated by innate and adaptive immune responses. Here we demonstrate that when epSPCs are cultured from rats with a SCI (ependymal stem/progenitor cells injury [epSPCi]), these cells proliferate 10 times faster in vitro than epSPC derived from control animals and display enhanced self renewal. Genetic profile analysis revealed an important influence of inflammation on signaling pathways in epSPCi after injury, including the upregulation of Jak/Stat and mitogen activated protein kinase pathways. Although neurospheres derived from either epSPCs or epSPCi differentiated efficiently to oligodendrocites and functional spinal motoneurons, a better yield of differentiated cells was consistently obtained from epSPCi cultures. Acute transplantation of undifferentiated epSPCi or the resulting oligodendrocyte precursor cells into a rat model of severe spinal cord contusion produced a significant recovery of motor activity 1 week after injury. These transplanted cells migrated long distances from the rostral and caudal regions of the transplant to the neurofilament-labeled axons in and around the lesion zone. Our findings demonstrate that modulation of endogenous epSPCs represents a viable cell-based strategy for restoring neuronal dysfunction in patients with spinal cord damage.
Thiocoraline is a thiodepsipeptide antitumor compound produced by two actinomycetes Micromonospora sp. ACM2‐092 and Micromonospora sp. ML1, isolated from two marine invertebrates (a soft coral and a mollusc) found of the Indian Ocean coast of Mozambique. By using oligoprimers derived from nonribosomal peptide synthetase (NRPS) consensus sequences, six PCR fragments containing putative NRPS adenylation domains were amplified from the chromosome of Micromonospora sp. ML1. Insertional inactivation of each adenylation domain showed that two of them generated nonproducing mutants, thereby indicating that these domains were involved in thiocoraline biosynthesis. Sequencing of a 64.6 kbp DNA region revealed the presence of 36 complete open reading frames (ORFs) and two incomplete ones. Heterologous expression of a region of about 53 kbp, containing 26 of the ORFs, in Streptomyces albus and S. lividans led to the production of thiocoraline in these streptomycetes. Surprisingly, the identified gene cluster contains more NRPS modules than expected on the basis of the number of amino acids of thiocoraline. TioR and TioS would most probably constitute the NRPS involved in the biosynthesis of the thiocoraline backbone, according to the colinearity of the respective modules. It is proposed that two other NRPSs, TioY and TioZ, could be responsible for the biosynthesis of a small peptide molecule which could be involved in regulation of the biosynthesis of thicoraline in Micromonospora sp. ML1. In addition, a pathway is proposed for the biosynthesis of the unusual starter unit, 3‐hydroxy‐quinaldic acid.
A 2.9-kilobase Acc I fragment of the DNA of the pneumococcal bacteriophage Cp-1, containing the cpl gene, hybridizes with the lyt4 gene encoding the pneumococcal amidase. The nucleotide sequence of the cpl gene of Cp-1, encoding a muramidase (CPL), has been determined. The 3' regions of the cpl and IytA coding sequences show considerable nucleotide sequence homology and the carboxyl-terminal domains of the deduced amino acid sequences of these lysins are quite similar: 73 of the carboxyl-terminal 142 amino acid residues are identical, and of the 69 substitutions, 55 are conservative. Comparisons between CPL, the pneumococcal amidase, and the muramidase of the fungus Chalaropsis sp.(an enzyme that also degrades the pneumococcal cell wall) strongly suggest that the carboxyl-terminal domains of CPL and of the amidase might be responsible for the specific recognition of choline-containing cell walls, as well as for the noncompetitive inhibition of the catalytic activity of these enzymes by the pneumococcal lipoteichoic acid or by high concentrations of choline. In addition, the active center of these enzymes should be located in their amino-terminal domains. Our results suggest an evolutionary relationship between phage and host lysins.
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