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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EDuring the Kidney Week 2014 Opening Plenary session pancreatic \u03b2 cells for tissue repair and regeneration in diabetic therapy were discussed.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Kidney Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Kidney Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENephrology\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EDouglas A. Melton, PhD, Howard Hughes Medical Institute, Cambridge, Massachusetts, USA presented the State-of-the-Art Lecture during the Opening Plenary session. The subject was making pancreatic \u03b2 cells for tissue repair and regeneration in diabetic therapy.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EThe injection of insulin with the intent of keeping blood sugar levels in the \u201cnormal range\u201d has been the only viable option for insulin-dependent diabetics since the 1920s. However, insulin injections do not cure diabetes and frequently result in costly complications, such as heart failure and peripheral neuropathy. Stem cell therapy has the potential to replace dysfunctional pancreatic insulin-producing \u03b2 cells and cure type 1 diabetes, which is the result of autoimmune destruction of \u03b2 cells in the pancreatic islet. Two programs have attempted to make pancreatic \u03b2 cells: direct reprogramming, which has only partially worked, and directed differentiation of stem cells (embryonic or induced pluripotent stem cells). Using the first approach, researchers attempt to reprogram the cell. In mice, the adult exocrine cells can be directly reprogrammed into insulin-producing cells by the expression of 3 transcription factors: Pdx1, Ngn3, and MafA. These developmental regulators reprogram differentiated pancreatic exocrine cells into cells that closely resemble endogenous islet \u03b2 cells that could provide insulin in response to a glucose challenge. Dr Melton has spent decades attempting to advance this technique without much success. He no longer believes that transdifferentiation is the best way to make new functional \u03b2 cells. Instead, he believes a better approach is to make pancreatic \u03b2 cells from embryonic (ES) or induced pluripotent stem cells through 4 stages of development.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003ESeveral investigators had been successful with using normal embryogenesis growth factors in differentiating human embryonic and pluripotent stem cells into cells that have features characteristic of kidney lineage cells [Lam AQ et al. \u003Cem\u003EJ Am Soc Nephrol\u003C\/em\u003E. 2014; Takasato M et al. \u003Cem\u003ENat Cell Biol\u003C\/em\u003E. 2014; Xia Y et al. \u003Cem\u003ENat Cell Biol\u003C\/em\u003E. 2013]. However, many challenges remain to achieve the goal of creating cells that can actually secrete insulin after glucose stimulation.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThe idea is to recapitulate the normal stepwise progression from embryonic pluripotent cells to definitive endoderm (DE), exocrine, pancreatic progenitors, and finally fully differentiated \u03b2 cells. DE and pancreatic progenitors can be differentiated a lot easier than other parts of the process. However, it has proven extremely difficult to move to the last stage, the development of fully differentiated \u03b2 cells. Dr Melton and his team developed a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive \u03b2 cells in a relatively short period of time.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe strategy entails sequential modulation of multiple signaling pathways in a three-dimensional cell culture system. Through a trial-and-error process, varying culture conditions, the application of growth factors, and the use of small molecules as signaling inducers, many combinations of signaling pathways and chemical modulators were tested to determine which chemicals modulate signals. This was performed without any transgenes or genetic modifications.\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EThe new differentiation process generated \u03b2 cells from human embryonic and pluripotent stem cells in a culture of hedgehog inhibitor SANT1, KFG, and a low concentration of retinoic acid to generate high levels of NKX6-1 + PDX1 + coexpressing pancreatic progenitor clusters. One of the tests of functioning \u03b2 cells is the cells\u0027 ability to secrete insulin when challenged by glucose (glucose-stimulated insulin secretion [GSIS]). Using this new process, the generated \u03b2 cells respond to multiple sequential glucose challenges similar to primary adult cadaveric islets (1\u003Csup\u003E0\u003C\/sup\u003E \u03b2 cells) and superior to polyhormonal (PH) cells. PH cells are in vitro differentiated human pluripotent stem cells that have immature or abnormal phenotypes, and they resemble human fetal but not adult \u03b2 cells. PH cells show neither GSIS nor other key properties of functioning \u03b2 cells. After sequential low- and high-glucose challenges, cells were depolarized with 30 mM KCl. Membrane depolarization causes an influx of calcium ions, which triggers insulin exocytosis [Mohammed JS et al. \u003Cem\u003ELab Chip\u003C\/em\u003E. 2009]\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EStem cell-derived \u03b2 (SC-\u03b2) and 1\u003Csup\u003E0\u003C\/sup\u003E \u03b2 cells respond to glucose challenges by increasing intracellular calcium more than PH cells. The new differentiation strategy creates SC-\u03b2 cells that can package and crystallize insulin protein into granules similar to 1\u003Csup\u003E0\u003C\/sup\u003E \u03b2 cells. The human SC-\u03b2 cells, when transplanted into the kidney capsule of a diabetic mouse, were secreting insulin into the bloodstream in a glucose-regulated manner similar to that of human islet cells.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EIn the diabetic mice receiving ES-\u03b2 cells, blood sugars were normalized, whereas animals receiving control cells showed progressively worsening hyperglycemia [Pagliuca FW et al. \u003Cem\u003ECell\u003C\/em\u003E. 2014]. The mice maintained human insulin secretion up to 18 weeks after transplantation and lived longer.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EThe screening of new drugs for diabetes is currently hindered by the supply of islets. A large consistent number of SC-\u03b2 cells would aid in the drug discovery process and would be useful for disease modeling of diabetes. The next challenge will be blocking the immune response for type 1 diabetes and transplantation of ES-\u03b2 cells into diabetic humans.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/49\/4\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022The editors would like to thank the many members of the American Society of Nephrology Kidney Week presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-342022105\u0022 data-figure-caption=\u0022The editors would like to thank the many members of the American Society of Nephrology Kidney Week presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure1\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/49\/4\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/49\/4\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/49\/4\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15301\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\n               \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003EThe editors would like to thank the many members of the American Society of Nephrology Kidney Week presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2015 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/49\/4.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzltsp\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzltsp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}