{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T19:00:35Z","timestamp":1784746835330,"version":"3.55.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      The engraftment of induced cells from human pluripotent stem cell\u2013derived cardiomyocytes (hiPSC-CMs) for myocardial infarction therapy is critically hindered by their low cell-cycle activity and survival rates. In this study, we explored the role of the long noncoding RNA activated by DNA damage (\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      ) in enhancing the cell-cycle activity and engraftment of hiPSC-CMs, providing new insights into myocardial repair.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      hiPSC-CMs overexpressing\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      (hiPSC-\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      <jats:sup>OE<\/jats:sup>\n                      CMs) were generated via lentiviral transduction using a cardiac-specific promoter, whereas\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      knockdown was achieved by small interfering RNA transfection. The effects of\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      on cell-cycle activity, nuclear DNA content, nuclear number, maturation, and apoptosis in hiPSC-CMs were examined in vitro using Western blot, reverse transcription quantitative polymerase chain reaction, immunofluorescence, and flow cytometry. In a murine myocardial infarction model, hiPSC-CMs overexpressing\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      were transplanted into the infarcted myocardium. Engraftment, cell-cycle activity, and infarct size were evaluated by immunofluorescence, and cardiac function was assessed by echocardiography. Furthermore, the molecular mechanisms underlying\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      -mediated regulation of hiPSC-CM cell-cycle activity were investigated, including its role in exosome-mediated paracrine effects on host cardiomyocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      overexpression significantly increased the percentages of Ki67 (antigen KI-67)-positive, PH3 (phosphorylated histone 3)-positive, Aurora B\u2013positive, and EdU (5-ethynyl-2\u2019-deoxyuridine)-positive cells. It also increased the proportion of diploid nuclei and mononucleated cells, induced a trend toward a less mature state, and reduced apoptosis in hiPSC-CMs. Transplantation of hiPSC-CMs overexpressing\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      improved myocardial repair, with greater cell-cycle activity of engrafted cells and endogenous cardiomyocytes in the myocardial infarction model. Mechanistically,\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      exerted its effects by sequestering PUM2 (pumilio RNA-binding protein family member 2), an RNA-binding protein, thereby alleviating its translational repression of\n                      <jats:italic toggle=\"yes\">MASTL<\/jats:italic>\n                      (microtubule-associated serine\/threonine kinase like), a key regulator of mitotic progression. Moreover, exosomes secreted by hiPSC-CMs overexpressing\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      promoted the cell-cycle activity of recipient cardiomyocytes, suggesting a possible paracrine contribution to myocardial repair.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      overexpression promoted cell-cycle progression via the PUM2\/\n                      <jats:italic toggle=\"yes\">MASTL<\/jats:italic>\n                      mRNA axis. Moreover, exosomes derived from these cells stimulated endogenous cardiomyocyte cell-cycle activity, contributing to myocardial repair. These findings underscore the therapeutic potential of\n                      <jats:italic toggle=\"yes\">NORAD<\/jats:italic>\n                      -modulated hiPSC-CMs for promoting myocardial repair.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.126.324431","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T09:00:38Z","timestamp":1782378038000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["<i>NORAD<\/i>\n                    Overexpression Enhances hiPSC-CM Regenerative Potency via PUM2\/\n                    <i>MASTL<\/i>\n                    Signaling"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8650-1639","authenticated-orcid":true,"given":"Kanghui","family":"Huan","sequence":"first","affiliation":[{"name":"Department of Cardiology, Binzhou Medical University Hospital, Binzhou Medical University, China (K.H., X.X., Y.C., W.B.)."},{"name":"Department of Pharmacy, Binzhou Medical University, Yantai, China (K.H., Y.J., W.X., X.D., S.L., Y.D., Y.Y., Y.S., W.B.)."},{"name":"Frontier Innovation Center, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China (K.H., S.Y., M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7827-2266","authenticated-orcid":true,"given":"Yujian","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Binzhou Medical University, Yantai, China (K.H., Y.J., W.X., X.D., S.L., Y.D., Y.Y., Y.S., W.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Binzhou Medical University Hospital, Binzhou Medical University, China (K.H., X.X., Y.C., W.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3685-1768","authenticated-orcid":true,"given":"Weifeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Binzhou Medical University, Yantai, China (K.H., Y.J., W.X., X.D., S.L., Y.D., Y.Y., Y.S., W.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3704-4421","authenticated-orcid":true,"given":"Xiaolei","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Binzhou Medical University, Yantai, China (K.H., Y.J., W.X., X.D., S.L., Y.D., Y.Y., Y.S., W.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3834-9879","authenticated-orcid":true,"given":"Sai","family":"Yao","sequence":"additional","affiliation":[{"name":"Frontier Innovation Center, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China (K.H., S.Y., M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4673-4459","authenticated-orcid":true,"given":"Yanli","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Binzhou Medical University Hospital, Binzhou Medical University, China (K.H., X.X., Y.C., W.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3930-0943","authenticated-orcid":true,"given":"Shaomeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Binzhou Medical University, Yantai, China (K.H., Y.J., W.X., X.D., S.L., Y.D., Y.Y., Y.S., W.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1288-6482","authenticated-orcid":true,"given":"Yanfang","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Binzhou Medical University, 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