{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:13:34Z","timestamp":1791825214750,"version":"4.3.4"},"reference-count":80,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,1,17]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      When human induced pluripotent stem cells (hiPSCs) that CCND2-OE (overexpressed cyclin-D2) were differentiated into cardiomyocytes (\n                      <jats:sup>CCND2-OE<\/jats:sup>\n                      hiPSC-CMs) and administered to the infarcted hearts of immunodeficient mice, the cells proliferated after administration and repopulated &gt;50% of the scar. Here, we knocked out human leukocyte antigen class I and class II expression in\n                      <jats:sup>CCND2-OE<\/jats:sup>\n                      hiPSC-CMs (\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CMs) to reduce the cells\u2019 immunogenicity and then assessed the therapeutic efficacy of\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CMs for the treatment of myocardial infarction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CM and wild-type hiPSC-CM (\n                      <jats:sup>WT<\/jats:sup>\n                      hiPSC-CM) spheroids were differentiated in shaking flasks, purified, characterized, and intramyocardially injected into pigs after ischemia\/reperfusion injury; control animals were injected with basal medium. Cardiac function was evaluated via cardiac magnetic resonance imaging, and cardiomyocyte proliferation was assessed via immunostaining and single-nucleus RNA sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Measurements of cardiac function and scar size were significantly better in pigs treated with\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CM spheroids than in animals treated with medium or\n                      <jats:sup>WT<\/jats:sup>\n                      hiPSC-CM spheroids.\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CMs were detected for just 1 week after administration, but assessments of cell cycle activity and proliferation were significantly higher in the endogenous pig cardiomyocytes of the hearts from the\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CM spheroid group than in those from the other 2 groups. Single-nucleus RNA-sequencing analysis identified a cluster of proliferating cardiomyocytes that was significantly more prevalent in the\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CM spheroid\u2013treated hearts (3.65%) than in the hearts from the medium (0.89%) or\n                      <jats:sup>WT<\/jats:sup>\n                      hiPSC-CM spheroid (1.33%) groups at week 1. YAP (Yes-associated protein) protein levels and nuclear localization were also significantly upregulated in pig cardiomyocytes after treatment with\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CM spheroids. Follistatin, which interacts with the HIPPO\/YAP pathway, was significantly more abundant in the medium from\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CM spheroids than\n                      <jats:sup>WT<\/jats:sup>\n                      hiPSC-CM spheroids (30.29\u00b12.39 versus 16.62\u00b10.83 ng\/mL,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.0056). Treatment with follistatin increased\n                      <jats:sup>WT<\/jats:sup>\n                      hiPSC-CM cell counts by 28.3% over 16 days in culture and promoted cardiomyocyte proliferation in the infarcted hearts of adult mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      <jats:sup>KO\/OE<\/jats:sup>\n                      hiPSC-CM spheroids significantly improved cardiac function and reduced infarct size in pig hearts after ischemia\/reperfusion injury by secreting follistatin, which upregulated HIPPO\/YAP signaling and proliferation in endogenous pig cardiomyocytes.\n                    <\/jats:p>\n                  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