Open Access The Impact of Stem Cells on Electron Fluxes, Proton Translocation, and ATP Synthesis in Kidney Mitochondria After Ischemia/Reperfusion

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Abstract:

Tissue damage by ischemia/reperfusion (I/R) results from a temporary cessation of blood flow followed by the restoration of circulation. The injury depresses mitochondrial respiration, increases the production of reactive oxygen species (ROS), decreases the mitochondrial transmembrane potential, and stimulates invasion by inflammatory cells. The primary objective of this work was to address the potential use of bone marrow stem cells (BMSCs) to preserve and restore mitochondrial function in the kidney after I/R. Mitochondria from renal proximal tubule cells were isolated by differential centrifugation from rat kidneys subjected to I/R (clamping of renal arteries followed by release of circulation after 30 min), without or with subcapsular administration of BMSCs. Respiration starting from mitochondrial complex II was strongly affected following I/R. However, when BMSCs were injected before ischemia or together with reperfusion, normal electron fluxes, electrochemical gradient for protons, and ATP synthesis were almost completely preserved, and mitochondrial ROS formation occurred at a low rate. In homogenates from cultured renal cells transiently treated with antimycin A, the coculture with BMSCs induced a remarkable increase in protein S-nitrosylation that was similar to that found in mitochondria isolated from I/R rats, evidence that BMSCs protected against both superoxide anion and peroxynitrite. Labeled BMSCs migrated to damaged tubules, suggesting that the injury functions as a signal to attract and host the injected BMSCs. Structural correlates of BMSC injection in kidney tissue included stimulus of tubule cell proliferation, inhibition of apoptosis, and decreased inflammatory response. Histopathological analysis demonstrated a score of complete preservation of tubular structures by BMSCs, associated with normal plasma creatinine and urinary osmolality. These key findings shed light on the mechanisms that explain, at the mitochondrial level, how stem cells prevent damage by I/R. The action of BMSCs on mitochondrial functions raises the possibility that autologous BMSCs may help prevent I/R injuries associated with transplantation and acute renal diseases.
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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.

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