Phosphatase, Mg<sup>2+</sup>/Mn<sup>2+</sup> dependent 1B regulates the hematopoietic stem cells homeostasis via the Wnt/β-catenin signaling
Zhiyuan Lu,
Hanzhi Yu,
Yanxia Li,
Guangsen Xu,
Xiaoxun Li,
Yongjun Liu,
Yuemao Shen,
Zhigang Cai,
Baobing Zhao
Affiliations
Zhiyuan Lu
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China, 250012; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; School of Pharmaceutical Sciences and Institute of Materia Medica, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 250117
Hanzhi Yu
The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China, 300070
Yanxia Li
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China, 250012; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012
Guangsen Xu
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China, 250012; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012
Xiaoxun Li
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China, 250012; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012
Yongjun Liu
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China, 250012; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012
Yuemao Shen
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China, 250012; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012
Zhigang Cai
The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China, 300070
Baobing Zhao
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China, 250012; NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China, 250012
Hematopoietic stem cells (HSCs) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance. How HSCs maintain the balance between activation and quiescence remains largely unknown. Herein, we found that Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b) is required for the expansion of phenotypic HSCs in vitro. By using a conditional knockout mouse model in which Ppm1b was specifically depleted in hematopoietic cells, we demonstrated that loss of Ppm1b impaired the HSC homeostasis and hematopoietic reconstitution. Ppm1b deficiency mice also exhibited B-cell leukocytopenia, which is due to the compromised commitment and proliferation of B-biased lymphoid progenitor cells from CLPs. With the aid of a small molecular inhibitor, we confirmed the roles of Ppm1b in adult hematopoiesis that phenocopied the effects with loss of Ppm1b. Furthermore, transcriptome profiling of Ppm1b-deficient HSCs revealed the disruptive quiescence of HSC. Mechanistically, Ppm1b interacted with β-catenin and mediated its dephosphorylation. Loss of Ppm1b led to the decrease of the active β- catenin (non-phosphorylated) that interrupted the Wnt/β-catenin signaling in HSC, which consequently suppressed HSC expansion. Together, our study identified an indispensable role of Ppm1b in regulating HSC homeostasis via Wnt/β-catenin pathway.
