Loss of Nupr1 promotes engraftment by tuning the quiescence threshold of hematopoietic stem cells via regulation of the p53-checkpoint pathway

Hematopoietic stem cells (HSC) are dominantly quiescent under homeostasis, which is a key mechanism of maintaining the HSC pool for life-long hematopoiesis. Dormant HSC are poised to be immediately activated in certain conditions and can return to quiescence after homeostasis has been regained. At present, the molecular networks of regulating the threshold of HSC dormancy, if existing, remain largely unknown. Here, we show that deletion of Nupr1, a gene preferentially expressed in HSC, activated quiescent HSC under homeostasis, which conferred a competitive engraftment advantage for these HSC without compromising their stemness or multi-lineage differentiation capacity in serial transplantation settings. Following an expansion protocol, the Nupr1(-/-) HSC proliferated more robustly than their wild-type counterparts in vitro. Nupr1 inhibits the expression of p53 and rescue of this inhibition offsets the engraftment advantage. Our data reveal a new role for Nupr1 as a regulator of HSC quiescence, which provides insights for accelerating the engraftment efficacy of HSC transplantation by targeting the HSC quiescence-controlling network.

Automated summary

The study reveals a new role for the Nupr1 gene in regulating the quiescence of hematopoietic stem cells (HSC), which can have implications for improving HSC transplantation efficacy. The deletion of the Nupr1 gene activates dormant HSC and provides a competitive advantage in transplantation without compromising their stemness or differentiation capacity. In addition, the inhibition of Nupr1 affects HSC proliferation and engraftment. This finding could contribute to enhancing the success of HSC transplantation.