Emerging evidence suggests that the intravenous injection of bone marrow-derived stromal cells (BMSC) improves renal function after acute tubular injury, but the mechanism of this effect is controversial. In this article, we confirm that intravenous infusion of male BMSC reduced the severity of cisplatin-induced acute renal failure in adult female mice. This effect was also seen when BMSC (or adipocyte-derived stromal cells (AdSC)), were given by intraperitoneal injection. Infusion of BMSC enhanced tubular cell proliferation after injury and decreased tubular cell apoptosis. Using the Y chromosome as a marker of donor stromal cells, examination of multiple kidney sections at one or four days after cell infusion failed to reveal any examples of stromal cells within the tubules, and only rare examples of stromal cells within the renal interstitium. Furthermore, conditioned media from cultured stromal cells induced migration and proliferation of kidney-derived epithelial cells and significantly diminished cisplatin-induced proximal tubule cell death in vitro. Intraperitoneal administration of this conditioned medium to mice injected with cisplatin diminished tubular cell apoptosis, increased survival, and limited renal injury. Thus, marrow stromal cells protect the kidney from toxic injury by secreting factors that limit apoptosis and enhance proliferation of the endogenous tubular cells, suggesting that transplantation of the cells themselves is not necessary. Identification of the stromal cell-derived protective factors may provide new therapeutic options to explore in humans with acute kidney injury.
No abstract
Glial fibrillary acidic protein (GFAP)+ cells give rise to new neurons in the neurogenic niches; whether they are able to generate neurons in the cortical parenchyma is not known. Here, we use genetic fate mapping to examine the progeny of GFAP+ cells after postnatal hypoxia, a model for the brain injury observed in premature children. Following hypoxia, immature cortical astroglia underwent a shift towards neuronal fate and generated cortical excitatory neurons that appeared synaptically integrated into the circuitry. Fate mapped cortical GFAP+ cells derived ex vivo from hypoxic, but not normoxic mice were able to form pluripotent, long-term self-renewing neurospheres. Similarly, exposure to low oxygen conditions in vitro induced stem cell-like potential in immature cortical GFAP+ cells. Our data support the conclusion that hypoxia promotes pluripotency in GFAP+ cells in the cortical parenchyma. Such plasticity possibly explains the cognitive recovery found in some preterm children.
Human Dmc1 protein, a meiosis-specific homolog of Escherichia coli RecA protein, has previously been shown to promote DNA homologous pairing and strand-exchange reactions that are qualitatively similar to those of RecA protein and Rad51. Human and yeast Rad51 proteins each form a nucleoprotein filament that is very similar to the filament formed by RecA protein. However, recent studies failed to find a similar filament made by Dmc1 but showed instead that this protein forms octameric rings and stacks of rings. These observations stimulated further efforts to elucidate the mechanism by which Dmc1 promotes the recognition of homology. Dmc1, purified to a state in which nuclease and helicase activities were undetectable, promoted homologous pairing and strand exchange as measured by fluorescence resonance energy transfer (FRET). Observations on the intermediates and products, which can be distinguished by FRET assays, provided direct evidence of a three-stranded synaptic intermediate. The effects of helix stability and mismatched base pairs on the recognition of homology revealed further that human Dmc1, like human Rad51, requires the preferential breathing of A⅐T base pairs for recognition of homology. We conclude that Dmc1, like human Rad51 and E. coli RecA protein, promotes homologous pairing and strand exchange by a ''synaptic pathway'' involving a three-stranded nucleoprotein intermediate, rather than by a ''helicase pathway'' involving the separation and reannealing of DNA strands.T wo kinds of macromolecular protein structures play prominent roles in homologous genetic recombination: toroids and filaments. Among the toroidal structures, the best understanding of the relation of function to structure exists for Escherichia coli RuvB protein, which forms a hexameric ATPase͞helicase. Two such hexameric rings, interacting with RuvA protein, drive the migration of Holliday structures, the 4-fold branched DNA intermediate formed after initial synapsis and processing have occurred. The consequence of this driven migration is the reciprocal exchange of a pair of like strands between two duplex molecules (1). Rings are also formed by the exonuclease of phage (2), the Erf protein of phage P22 (3), and human Rad52 protein (4, 5). On the basis of the crystal structure of toroidal exonuclease, Kovall and Matthews suggested a mechanistic explanation of the high processivity of this enzyme (2).Some recombination proteins form both rings and filaments: the  protein of phage forms large rings and left-handed helical filaments (6).  protein promotes annealing of complementary single strands (7,8) and migration of a single-stranded branch (9). This protein, which does not hydrolyze ATP, binds more strongly to the product of its annealing activity, which may help to explain how it drives branch migration (10), but there are no correlations of structure with function that help us to understand the role of either the rings or the left-handed filaments. RecT protein, the product of a cryptic prophage in E. coli and a functional ...
Studies of rad52 mutants in Saccharomyces cerevisiae have revealed a critical role of Rad52 protein in double-strand break repair and meiosis, and roles in both RAD51-dependent and -independent pathways of recombination. In vitro, both yeast and human Rad52 proteins play auxiliary roles with RPA in the action of Rad51. Rad52 also has annealing activity and promotes the formation of D-loops in superhelical DNA. The experiments described here show that Homo sapiens (Hs)Rad52 and yeast Rad52 proteins promote strand exchange as well. Strand exchange was promoted by the Nterminal domain of HsRad52 that contains residues 1-237, which includes the residues required to form rings of Rad52, whereas other truncated domains, both N-terminal and C-terminal, were inactive. For both yeast Rad52 and HsRad52, the yield of strandexchange reactions was proportional to the fractional A⅐T content of the DNA substrates, but both enzymes catalyzed exchange with substrates that contained up to at least 50% G⅐C. Observations made on S. cerevisiae Rad52 protein from mutants with severe recombination deficiencies indicate that the strand-exchange activity measured in vitro reflects a biologically significant property of Rad52 protein.
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