Loss of Nupr1 promotes engraftment by tuning the dormancy threshold of hematopoietic stem cell repository via regulating p53-checkpoint pathway

Hematopoietic stem cells (HSCs) are dominantly quiescent under homeostasis, which is a key mechanism of maintaining the HSC pool for life-long hematopoiesis. Dormant HSCs poise to be immediately activated on urgent conditions and can return to dormancy after regaining homeostasis. To date, the molecular networks of regulating the threshold of HSC dormancy, if exist, remain largely unknown. Here, we unveiled that deletion of Nupr1, a gene preferentially expressed in HSCs, activated the dormant HSCs under homeostatic status, which conferred engraftment competitive advantage on HSCs without compromising their stemness and multi-lineage differentiation abilities in serial transplantation settings. Following an expansion protocol, the Nupr1-/- HSCs proliferate more robustly than their wild type counterparts in vitro. Nupr1 inhibits the expression of p53 via an unknown mechanism and the rescue of which offsets the engraftment advantage. Our data unveil the de novo role of Nupr1 as an HSC dormancy-regulator, which provides insights into accelerating the engraftment efficacy of HSC transplantation by targeting the HSC dormancy-controlling network.