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Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):154-166
Loss of Nupr1 promotes engraftment by tuning the quiescence threshold of hematopoietic stem cells via regulation of the p53-checkpoint pathway
Tongjie Wang,1,2,3,* Chengxiang Xia,1,3,* Qitong Weng,1 Kaitao Wang,1 Yong Dong,1 Sha Hao,4 Fang Dong,4 Xiaofei Liu,1 Lijuan Liu,1 Yang Geng,1 Yuxian Guan,1 Juan Du,1 Tao Cheng,4 Hui Cheng4 and Jinyong Wang1,2,3
1State Key Laboratory of Experimental Hematology, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou; 2Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou; 3Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou and 4State Key Laboratory of Experimental Hematology & National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
*TJW and CXX contributed equally as co-first authors.
ABSTRACT
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 counter- parts in vitro. Nupr1 inhibits the expression of p53 and rescue of this inhi- bition 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 target- ing the HSC quiescence-controlling network.
Introduction
Hematopoietic stem cells (HSC), the seeds of the adult blood system, generate all the blood lineages via hierarchical hematopoiesis. Under steady-state, the majority of HSC are maintained in quiescence, providing a pool of HSC for life-long hematopoiesis.1 However, the dormant HSC can be rapidly activated for stress hematopoiesis in emergency conditions, such as excessive blood loss, radiation injury, and chemotherapy damage.2 Mounting evidence points to the existence of an intrinsic molecular machinery of regulating HSC dormancy. In haploinsufficient Gata2+/- mice, there is a slight increase of quiescent HSC in conditions of homeosta- sis.3 Dnmt3a-knockout HSC have increased self-renewal ability and their number in the bone marrow is increased.4,5 JunB inactivation deregulates the cell-cycle machin- ery and reduces quiescent HSC.6 Hif-1a-deficient mice also show a decrease in dor- mant HSC.7 Conditional knockout of cylindromatosis (CYLD) induces dormant HSC to exit quiescence and abrogates their repopulating and self-renewal potential.8 CDK6, a protein not expressed in long-term HSC but present in short-term HSC, regulates exit from quiescence in human HSC, and overexpression of this protein promotes engraftment.9 Nevertheless, the underlying signaling regulatory network of HSC quiescence remains largely unknown.
Hematopoiesis
Correspondence:
JINYONG WANG
wang_jinyong@gibh.ac.cn
HUI CHENG
chenghui@ihcams.ac.cn
Received: September 24, 2019. Accepted: November 25, 2020. Pre-published: December 10, 2020.
https://doi.org/10.3324/haematol.2019.239186 ©2022 Ferrata Storti Foundation
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