{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:58:56Z","timestamp":1790755136326,"version":"4.1.0"},"reference-count":43,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T00:00:00Z","timestamp":1477958400000},"content-version":"vor","delay-in-days":244,"URL":"http:\/\/www.diabetesjournals.org\/site\/license"}],"funder":[{"DOI":"10.13039\/100001167","name":"Larry L. Hillblom Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001167","id-type":"DOI","asserted-by":"crossref"}]},{"name":"JDRF"},{"name":"JDRF"},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"name":"JDRF"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,5,1]]},"abstract":"<jats:p>Diabetes is associated with loss of functional pancreatic \u03b2-cells, and restoration of \u03b2-cells is a major goal for regenerative therapies. Endogenous regeneration of \u03b2-cells via \u03b2-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous \u03b2-cells have been elusive. The regenerative capacity of \u03b2-cells declines rapidly with age, due to accumulation of p16INK4a, resulting in limited capacity for adult endocrine pancreas regeneration. Here, we show that transforming growth factor-\u03b2 (TGF-\u03b2) signaling via Smad3 integrates with the trithorax complex to activate and maintain Ink4a expression to prevent \u03b2-cell replication. Importantly, inhibition of TGF-\u03b2 signaling can result in repression of the Ink4a\/Arf locus, resulting in increased \u03b2-cell replication in adult mice. Furthermore, small molecule inhibitors of the TGF-\u03b2 pathway promote \u03b2-cell replication in human islets transplanted into NOD-scid IL-2Rgnull mice. These data reveal a novel role for TGF-\u03b2 signaling in the regulation of the Ink4a\/Arf locus and highlight the potential of using small molecule inhibitors of TGF-\u03b2 signaling to promote human \u03b2-cell replication.<\/jats:p>","DOI":"10.2337\/db15-1331","type":"journal-article","created":{"date-parts":[[2016,3,3]],"date-time":"2016-03-03T03:53:31Z","timestamp":1456977211000},"page":"1208-1218","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":107,"title":["Inhibition of TGF-\u03b2 Signaling Promotes Human Pancreatic \u03b2-Cell Replication"],"prefix":"10.2337","volume":"65","author":[{"given":"Sangeeta","family":"Dhawan","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ercument","family":"Dirice","sequence":"additional","affiliation":[{"name":"Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit N.","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Islet Cell and Regenerative Biology, Joslin Diabetes Center and Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil","family":"Bhushan","sequence":"additional","affiliation":[{"name":"Diabetes Center, University of California, San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2016,3,2]]},"reference":[{"key":"2022031211311451400_B1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nature02520","article-title":"Adult pancreatic beta-cells are formed by self-duplication rather than 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