Growth Inhibitors Promote Differentiation of Insulin-Producing Tissue from Embryonic Stem Cells
The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2002-12, Vol.99 (25), p.16105-16110 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Hori, Yuichi Rulifson, Ingrid C. Tsai, Bernette C. Heit, Jeremy J. Cahoy, John D. Kim, Seung K. |
| description | The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic β cells in several ways. These cells aggregated in structures similar, but not identical, to pancreatic islets of Langerhans, produced insulin at levels far greater than previously reported, and displayed glucose-dependent insulin release in vitro. Transplantation of these cell aggregates increased circulating insulin levels, reduced weight loss, improved glycemic control, and completely rescued survival in mice with diabetes mellitus. Graft removal resulted in rapid relapse and death. Graft analysis revealed that transplanted insulin-producing cells remained differentiated, enlarged, and did not form detectable tumors. These results provide evidence that embryonic stem cells can serve as the source of insulin-producing replacement tissue in an experimental model of diabetes mellitus. Strategies for producing cells that can replace islet functions described here can be adapted for similar uses with human cells. |
| doi_str_mv | 10.1073/pnas.252618999 |
| format | Article |
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We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic β cells in several ways. These cells aggregated in structures similar, but not identical, to pancreatic islets of Langerhans, produced insulin at levels far greater than previously reported, and displayed glucose-dependent insulin release in vitro. Transplantation of these cell aggregates increased circulating insulin levels, reduced weight loss, improved glycemic control, and completely rescued survival in mice with diabetes mellitus. Graft removal resulted in rapid relapse and death. Graft analysis revealed that transplanted insulin-producing cells remained differentiated, enlarged, and did not form detectable tumors. These results provide evidence that embryonic stem cells can serve as the source of insulin-producing replacement tissue in an experimental model of diabetes mellitus. Strategies for producing cells that can replace islet functions described here can be adapted for similar uses with human cells.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.252618999</identifier><identifier>PMID: 12441403</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Androstadienes - pharmacology ; Animals ; Biological Sciences ; Biology ; Biomarkers ; Cell Aggregation ; Cell Differentiation - drug effects ; Cell Line - cytology ; Cell Line - drug effects ; Cell Line - metabolism ; Cell Line - transplantation ; Cell lines ; Diabetes mellitus ; Diabetes Mellitus, Experimental - blood ; Diabetes Mellitus, Experimental - therapy ; Diabetes Mellitus, Type 1 - blood ; Diabetes Mellitus, Type 1 - therapy ; Embryo, Mammalian - cytology ; Embryonic stem cells ; Enzyme Inhibitors - pharmacology ; Glucagon - biosynthesis ; Growth Inhibitors - pharmacology ; Homeostasis ; Insulin ; Insulin - biosynthesis ; Insulin - blood ; Insulin - metabolism ; Insulin Secretion ; Islets of Langerhans ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasms, Experimental - etiology ; Neurons ; Niacinamide - pharmacology ; Pancreatic cells ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - physiology ; Stem Cell Transplantation - adverse effects ; Stem cells ; Stem Cells - cytology ; Stem Cells - drug effects ; Stem Cells - metabolism ; Streptozocin ; Tissue grafting ; Transplantation ; Weight Loss ; Wortmannin</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2002-12, Vol.99 (25), p.16105-16110</ispartof><rights>Copyright 1993-2002 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Dec 10, 2002</rights><rights>Copyright © 2002, The National Academy of Sciences 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c587t-3f6283a7332424deb6f0f44bbedbbba2e4abc0bed84c31a36506236c4cff3a9a3</citedby><cites>FETCH-LOGICAL-c587t-3f6283a7332424deb6f0f44bbedbbba2e4abc0bed84c31a36506236c4cff3a9a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/99/25.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3073915$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3073915$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12441403$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hori, Yuichi</creatorcontrib><creatorcontrib>Rulifson, Ingrid C.</creatorcontrib><creatorcontrib>Tsai, Bernette C.</creatorcontrib><creatorcontrib>Heit, Jeremy J.</creatorcontrib><creatorcontrib>Cahoy, John D.</creatorcontrib><creatorcontrib>Kim, Seung K.</creatorcontrib><title>Growth Inhibitors Promote Differentiation of Insulin-Producing Tissue from Embryonic Stem Cells</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic β cells in several ways. These cells aggregated in structures similar, but not identical, to pancreatic islets of Langerhans, produced insulin at levels far greater than previously reported, and displayed glucose-dependent insulin release in vitro. Transplantation of these cell aggregates increased circulating insulin levels, reduced weight loss, improved glycemic control, and completely rescued survival in mice with diabetes mellitus. Graft removal resulted in rapid relapse and death. Graft analysis revealed that transplanted insulin-producing cells remained differentiated, enlarged, and did not form detectable tumors. These results provide evidence that embryonic stem cells can serve as the source of insulin-producing replacement tissue in an experimental model of diabetes mellitus. Strategies for producing cells that can replace islet functions described here can be adapted for similar uses with human cells.</description><subject>Androstadienes - pharmacology</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Cell Aggregation</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Line - cytology</subject><subject>Cell Line - drug effects</subject><subject>Cell Line - metabolism</subject><subject>Cell Line - transplantation</subject><subject>Cell lines</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - blood</subject><subject>Diabetes Mellitus, Experimental - therapy</subject><subject>Diabetes Mellitus, Type 1 - blood</subject><subject>Diabetes Mellitus, Type 1 - therapy</subject><subject>Embryo, Mammalian - cytology</subject><subject>Embryonic stem cells</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glucagon - biosynthesis</subject><subject>Growth Inhibitors - pharmacology</subject><subject>Homeostasis</subject><subject>Insulin</subject><subject>Insulin - biosynthesis</subject><subject>Insulin - blood</subject><subject>Insulin - metabolism</subject><subject>Insulin Secretion</subject><subject>Islets of Langerhans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Neoplasms, Experimental - etiology</subject><subject>Neurons</subject><subject>Niacinamide - pharmacology</subject><subject>Pancreatic cells</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - physiology</subject><subject>Stem Cell Transplantation - adverse effects</subject><subject>Stem cells</subject><subject>Stem Cells - cytology</subject><subject>Stem Cells - drug effects</subject><subject>Stem Cells - metabolism</subject><subject>Streptozocin</subject><subject>Tissue grafting</subject><subject>Transplantation</subject><subject>Weight Loss</subject><subject>Wortmannin</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks9vFCEUx4nR2LV69WR04sH0Miu_BoaDB7PW2qSJJtYzARa6bGZgBca2_71sdrvaHvREyPt8H9_3vgDwEsE5gpy83wSV57jDDPVCiEdghqBALaMCPgYzCDFve4rpEXiW8xpCKLoePgVHCFOKKCQzIM9SvC6r5jysvPYlptx8S3GMxTafvHM22VC8Kj6GJrpK5Wnwoa3IcjI-XDWXPufJNq5qmtNRp9sYvGm-Fzs2CzsM-Tl44tSQ7Yv9eQx-fD69XHxpL76enS8-XrSm63lpiWO4J4oTgqvdpdXMQUep1naptVbYUqUNrLeeGoIUYR1kmDBDjXNECUWOwYdd382kR7s01XZSg9wkP6p0K6Py8n4l-JW8ir8kIn3HcdW_2-tT_DnZXOTos6kTqGDjlCXHnLGe8v-CSHDGYU8r-PYBuI5TCnUJEkNEEYIdq9B8B5kUc07WHRwjKLcBy23A8hBwFbz-e84_-D7RCrzZA1vhXVmI2kMiVh-txMm_CemmYSj2plT01Q5d5_o1DiypxgTqyG_AY8WV</recordid><startdate>20021210</startdate><enddate>20021210</enddate><creator>Hori, Yuichi</creator><creator>Rulifson, Ingrid C.</creator><creator>Tsai, Bernette C.</creator><creator>Heit, Jeremy J.</creator><creator>Cahoy, John D.</creator><creator>Kim, Seung K.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20021210</creationdate><title>Growth Inhibitors Promote Differentiation of Insulin-Producing Tissue from Embryonic Stem Cells</title><author>Hori, Yuichi ; Rulifson, Ingrid C. ; Tsai, Bernette C. ; Heit, Jeremy J. ; Cahoy, John D. ; Kim, Seung K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c587t-3f6283a7332424deb6f0f44bbedbbba2e4abc0bed84c31a36506236c4cff3a9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Androstadienes - pharmacology</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>Biology</topic><topic>Biomarkers</topic><topic>Cell Aggregation</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Line - cytology</topic><topic>Cell Line - drug effects</topic><topic>Cell Line - metabolism</topic><topic>Cell Line - transplantation</topic><topic>Cell lines</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - blood</topic><topic>Diabetes Mellitus, Experimental - therapy</topic><topic>Diabetes Mellitus, Type 1 - blood</topic><topic>Diabetes Mellitus, Type 1 - therapy</topic><topic>Embryo, Mammalian - cytology</topic><topic>Embryonic stem cells</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glucagon - biosynthesis</topic><topic>Growth Inhibitors - pharmacology</topic><topic>Homeostasis</topic><topic>Insulin</topic><topic>Insulin - biosynthesis</topic><topic>Insulin - blood</topic><topic>Insulin - metabolism</topic><topic>Insulin Secretion</topic><topic>Islets of Langerhans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Neoplasms, Experimental - etiology</topic><topic>Neurons</topic><topic>Niacinamide - pharmacology</topic><topic>Pancreatic cells</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphatidylinositol 3-Kinases - physiology</topic><topic>Stem Cell Transplantation - adverse effects</topic><topic>Stem cells</topic><topic>Stem Cells - cytology</topic><topic>Stem Cells - drug effects</topic><topic>Stem Cells - metabolism</topic><topic>Streptozocin</topic><topic>Tissue grafting</topic><topic>Transplantation</topic><topic>Weight Loss</topic><topic>Wortmannin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hori, Yuichi</creatorcontrib><creatorcontrib>Rulifson, Ingrid C.</creatorcontrib><creatorcontrib>Tsai, Bernette C.</creatorcontrib><creatorcontrib>Heit, Jeremy J.</creatorcontrib><creatorcontrib>Cahoy, John D.</creatorcontrib><creatorcontrib>Kim, Seung K.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Biotechnology Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hori, Yuichi</au><au>Rulifson, Ingrid C.</au><au>Tsai, Bernette C.</au><au>Heit, Jeremy J.</au><au>Cahoy, John D.</au><au>Kim, Seung K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Growth Inhibitors Promote Differentiation of Insulin-Producing Tissue from Embryonic Stem Cells</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2002-12-10</date><risdate>2002</risdate><volume>99</volume><issue>25</issue><spage>16105</spage><epage>16110</epage><pages>16105-16110</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic β cells in several ways. These cells aggregated in structures similar, but not identical, to pancreatic islets of Langerhans, produced insulin at levels far greater than previously reported, and displayed glucose-dependent insulin release in vitro. Transplantation of these cell aggregates increased circulating insulin levels, reduced weight loss, improved glycemic control, and completely rescued survival in mice with diabetes mellitus. Graft removal resulted in rapid relapse and death. Graft analysis revealed that transplanted insulin-producing cells remained differentiated, enlarged, and did not form detectable tumors. These results provide evidence that embryonic stem cells can serve as the source of insulin-producing replacement tissue in an experimental model of diabetes mellitus. Strategies for producing cells that can replace islet functions described here can be adapted for similar uses with human cells.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>12441403</pmid><doi>10.1073/pnas.252618999</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Androstadienes - pharmacology Animals Biological Sciences Biology Biomarkers Cell Aggregation Cell Differentiation - drug effects Cell Line - cytology Cell Line - drug effects Cell Line - metabolism Cell Line - transplantation Cell lines Diabetes mellitus Diabetes Mellitus, Experimental - blood Diabetes Mellitus, Experimental - therapy Diabetes Mellitus, Type 1 - blood Diabetes Mellitus, Type 1 - therapy Embryo, Mammalian - cytology Embryonic stem cells Enzyme Inhibitors - pharmacology Glucagon - biosynthesis Growth Inhibitors - pharmacology Homeostasis Insulin Insulin - biosynthesis Insulin - blood Insulin - metabolism Insulin Secretion Islets of Langerhans Male Mice Mice, Inbred NOD Mice, SCID Neoplasms, Experimental - etiology Neurons Niacinamide - pharmacology Pancreatic cells Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - physiology Stem Cell Transplantation - adverse effects Stem cells Stem Cells - cytology Stem Cells - drug effects Stem Cells - metabolism Streptozocin Tissue grafting Transplantation Weight Loss Wortmannin |
| title | Growth Inhibitors Promote Differentiation of Insulin-Producing Tissue from Embryonic Stem Cells |
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