JARID2 Inhibition Reprograms Human Hematopoietic Progenitor Cells To Enhance Bone Marrow Transplantation

Hematopoietic stem cell transplantation is a common treatment for many blood disorders. Umbilical cord blood (UCB) serves as a valuable source of hematopoietic stem and progenitor cells (HSPCs), particularly for patients lacking a matched donor. However, the limited number of repopulating cells in UCB units restricts its clinical utility. Here, we demonstrate that JARID2 knockdown, distinct from EZH2 loss, increases both the number and functionality of human UCB-derived HSPCs in vitro and in vivo. After ex vivo culture, these functionally enhanced HSPCs were identified as CD34?CD90?EPCR?CD49f?CD71?. Mechanistically, JARID2 knockdown promotes a quiescent, long-term self-renewal gene expression program by upregulating STAT1 and MHC class II. Notably, it also confers HSC-like potential to multipotent progenitors (MPPs), enhancing their regenerative capacity. These findings support JARID2 inhibition as a safe and reversible strategy to expand functional HSPCs from UCB ex vivo, potentially increasing access to this life-saving therapy for a broader patient population. Overall design: To investigate the molecular mechanisms underlying JARID2-KD–mediated HSPC expansion and functional enhancement, we transduced enriched human CD34? cells from umbilical cord blood with shRenilla, shJARID2, or shEZH2, and sorted hCD34? cells for CITE-seq after 8 days of ex vivo culture. Based on CITE-seq results and other functional assays, we further sorted CD34?CD90?EPCR?CD49f?CD71?GFP? cells after 8 days of ex vivo culture for bulk RNA-seq and CUT&Tag or CUT&RUN analysis. For scRNA-seq analysis, we transplanted CD34? cells transduced with shRenilla or shJARID2 into NSG mice and collected hCD34? cells from the bone marrow 20 weeks post-transplantation.