{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:51:00Z","timestamp":1777510260243,"version":"3.51.4"},"reference-count":38,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2013,7,10]],"date-time":"2013-07-10T00:00:00Z","timestamp":1373414400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Cellular Reprogramming"],"published-print":{"date-parts":[[2013,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Recent studies have suggested that epigenetic modulation with chromatin-modifying agents can induce stemness and dedifferentiation and increase developmental plasticity. For instance, valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has been shown to promote self-renewal\/expansion of hematopoietic stem cells and facilitate the generation of induced pluripotent stem cells (iPSCs). Previously, we observed that downregulation of embryonic renal stem\/progenitor genes in the adult kidney was associated, at least in part, with epigenetic silencing. Therefore, we hypothesized that VPA may alter the expression of these genes and reprogram mature human adult kidney epithelial cells (hKEpCs) to a stem\/progenitor-like state.<\/jats:p>\n                  <jats:p>\n                    Here, using quantitative RT-PCR and flow cytometry [fluorescence-activated cell sorting (FACS)] analysis, we show in VPA-treated primary cultures of human adult and fetal kidney significant reinduction of the renal stem\/progenitor markers\n                    <jats:italic toggle=\"yes\">SIX2<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">OSR1<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">SALL1<\/jats:italic>\n                    , NCAM, and PSA-NCAM. Robust\n                    <jats:italic toggle=\"yes\">SIX2<\/jats:italic>\n                    mRNA re-expression was confirmed at the protein level by western blot and was associated with epigenetic changes of the histones at multiple sites of the\n                    <jats:italic toggle=\"yes\">SIX2<\/jats:italic>\n                    promoter leading to gene activation, significantly increased acetylation of histones H4, and methylation of lysine 4 on H3. Furthermore, we could demonstrate synergistic effects of VPA and Wnt antagonists on\n                    <jats:italic toggle=\"yes\">SIX2<\/jats:italic>\n                    and also\n                    <jats:italic toggle=\"yes\">OSR1<\/jats:italic>\n                    reinduction. Nevertheless, VPA resulted in upregulation of\n                    <jats:italic toggle=\"yes\">E-CADHERIN<\/jats:italic>\n                    and reduction in\n                    <jats:italic toggle=\"yes\">VIMENTIN<\/jats:italic>\n                    , preventing the skewing of hKEpCs towards a more replicative mesenchymal state required for clonogenic expansion and acquisition of stem cell characters, altogether inducing cell senescence at early passages. These results demonstrating that chromatin-modifying agents prevent dedifferentiation of hKEpCs have important clinical implications as they may limit\n                    <jats:italic toggle=\"yes\">ex-vivo<\/jats:italic>\n                    self-renewal\/expansion and possibly the\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    renal regenerative capacity initiated by dedifferentiation.\n                  <\/jats:p>","DOI":"10.1089\/cell.2012.0087","type":"journal-article","created":{"date-parts":[[2018,7,30]],"date-time":"2018-07-30T18:26:59Z","timestamp":1532975219000},"page":"281-292","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":16,"title":["Chromatin-Modifying Agents Reactivate Embryonic Renal Stem\/Progenitor Genes in Human Adult Kidney Epithelial Cells but Abrogate Dedifferentiation and Stemness"],"prefix":"10.1177","volume":"15","author":[{"given":"Dorit","family":"Omer","sequence":"first","affiliation":[{"name":"Sheba Medical Center","place":["Israel"]},{"name":"Tel Aviv University","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orit","family":"Harari-Steinberg","sequence":"additional","affiliation":[{"name":"Sheba Medical Center","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ella","family":"Buzhor","sequence":"additional","affiliation":[{"name":"Sheba Medical Center","place":["Israel"]},{"name":"Tel Aviv University","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally","family":"Metsuyanim","sequence":"additional","affiliation":[{"name":"Sheba Medical Center","place":["Israel"]},{"name":"Bar-Ilan University","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oren","family":"Pleniceanu","sequence":"additional","affiliation":[{"name":"Sheba Medical Center","place":["Israel"]},{"name":"Tel Aviv University","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adi","family":"Zundelevich","sequence":"additional","affiliation":[{"name":"Sheba Medical Center","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Einav Nili","family":"Gal-Yam","sequence":"additional","affiliation":[{"name":"Sheba Medical Center","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Dekel","sequence":"additional","affiliation":[{"name":"Sheba Medical Center","place":["Israel"]},{"name":"Tel Aviv University","place":["Israel"]},{"name":"Sheba Medical Center","place":["Israel"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2013,7,10]]},"reference":[{"key":"e_1_3_3_2_1","article-title":"Expression of NCAM recapitulates tubulogenic development in kidneys recovering from acute ischemia","volume":"277","author":"Abbate M.","year":"1999","unstructured":"Abbate M., , Brown D., , Bonventre J.V. 1999. Expression of NCAM recapitulates tubulogenic development in kidneys recovering from acute ischemia. Am. J. Physiol., 277:F454\u2013463.","journal-title":"Am. J. 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