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Umbilical cord blood (UCB) serves as a valuable source of hematopoietic stem and progenitor cells (HSPCs) for transplantation, particularly for patients lacking a matched donor. However, the limited number of repopulating cells in UCB units restricts its clinical utility. Our prior studies showed that genetic deletion of the polycomb repressive complex 2 (PRC2) co-factor\n                  <jats:italic>Jarid2<\/jats:italic>\n                  in mouse multipotent progenitors (MPPs) conveyed ectopic self-renewal capacity. Here, we hypothesized that the function of human HSPCs could be enhanced through\n                  <jats:italic>JARID2<\/jats:italic>\n                  inhibition. In this study, we demonstrate that both constitutive and transient knockdown of\n                  <jats:italic>JARID2<\/jats:italic>\n                  increases the number and enhances the functionality of human HSPCs both\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . This phenotype was distinct from inhibition of\n                  <jats:italic>EZH2<\/jats:italic>\n                  in UCB cells, suggesting the mechanism was independent of PRC2 co-factor activity of JARID2. Mechanistically,\n                  <jats:italic>JARID2<\/jats:italic>\n                  knockdown promotes a quiescent, long-term self-renewal gene expression program governed by upregulating\n                  <jats:italic>STAT1<\/jats:italic>\n                  and characterized by an MHC class II immunophenotype. Analogous to mice, these mechanisms conferred HSC-like potential to human MPPs\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Taken together, these findings highlight\n                  <jats:italic>JARID2<\/jats:italic>\n                  inhibition as a novel and reversible approach to expand functional UCB-derived HSPCs ex vivo, potentially improving access to stem cell transplantation for a wider patient population.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    Genetic inhibition of\n                    <jats:italic>JARID2<\/jats:italic>\n                    enhances repopulating activity of human hematopoietic stem and progenitor cells\n                    <jats:italic>in vivo<\/jats:italic>\n                    via\n                    <jats:italic>STAT1<\/jats:italic>\n                    upregulation.\n                  <\/jats:p>\n                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