Česká Genetická Banka

NATURE MEDICINE: 4/2013

NATURE MEDICINE: Regeneration and experimental orthotopic transplantation of a bioengineered kidney

"Approximately 100,000 individuals in the United States currently await kidney transplantation, and 400,000 individuals live with end-stage kidney disease requiring hemodialysis. The creation of a transplantable graft to permanently replace kidney function would address donor organ shortage and the morbidity associated with immunosuppression. Such a bioengineered graft must have the kidney's architecture and function and permit perfusion, filtration, secretion, absorption and drainage of urine. We decellularized rat, porcine and human kidneys by detergent perfusion, yielding acellular scaffolds with vascular, cortical and medullary architecture, a collecting system and ureters. To regenerate functional tissue, we seeded rat kidney scaffolds with epithelial and endothelial cells and perfused these cell-seeded constructs in a whole-organ bioreactor. The resulting grafts produced rudimentary urine in vitro when perfused through their intrinsic vascular bed. When transplanted in an orthotopic position in rat, the grafts were perfused by the recipient's circulation and produced urine through the ureteral conduit in vivo."

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3154.html

 

SCIENCE: Trachea Transplants Test the Limits

"June 2008 was the first time a patient received a trachea transplant that made use of her own stem cells, in what was then the most advanced example of tissue engineering. Since then, 14 other patients have received bioengineered tracheas. Some observers wonder if the surgeries are really examples of successful tissue engineering that utilize the special abilities of stem cells or an elaborate temporary fix that is destined to fail. Two surgeons are trying to address the doubts of their approach with clinical trials, but others contend that, before pushing ahead, the trachea pioneers should focus on understanding what happens to the grafts over the long term."

http://www.sciencemag.org/content/340/6130/266.summary

 

NATURE: Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization

"The PARKIN ubiquitin ligase (also known as PARK2) and its regulatory kinase PINK1 (also known as PARK6), often mutated in familial early-onset Parkinson’s disease, have central roles in mitochondrial homeostasis and mitophagy^{1, 2, 3}. Whereas PARKIN is recruited to the mitochondrial outer membrane (MOM) upon depolarization via PINK1 action and can ubiquitylate porin, mitofusin and Miro proteins on the MOM^{1, 4, 5, 6, 7, 8, 9, 10, 11}, the full repertoire of PARKIN substrates—the PARKIN-dependent ubiquitylome—remains poorly defined. Here we use quantitative diGly capture proteomics (diGly)^{12, 13} to elucidate the ubiquitylation site specificity and topology of PARKIN-dependent target modification in response to mitochondrial depolarization. Hundreds of dynamically regulated ubiquitylation sites in dozens of proteins were identified, with strong enrichment for MOM proteins, indicating that PARKIN dramatically alters the ubiquitylation status of the mitochondrial proteome. Using complementary interaction proteomics, we found depolarization-dependent PARKIN association with numerous MOM targets, autophagy receptors, and the proteasome. Mutation of the PARKIN active site residue C431, which has been found mutated in Parkinson’s disease patients, largely disrupts these associations. Structural and topological analysis revealed extensive conservation of PARKIN-dependent ubiquitylation sites on cytoplasmic domains in vertebrate and Drosophila melanogaster MOM proteins. These studies provide a resource for understanding how the PINK1–PARKIN pathway re-sculpts the proteome to support mitochondrial homeostasis."

http://www.nature.com/nature/journal/v496/n7445/full/nature12043.html

 

CELL BIOLOGY: Super-enhancers rule genes

"The myriad biomolecules that regulate gene expression are governed by an unanticipated layer of control. Researchers led by Richard Young at the Massachusetts Institute of Technology in Cambridge have found assemblies of enhancers — segments of DNA that associate with regulatory proteins and attach to genes to switch them on — that they…"

http://www.nature.com/nature/journal/v496/n7445/full/496273b.html