Page 130 - Haematologica Vol. 109 - July 2024

ARTICLE - Hematopoiesis
Phosphatase, Mg2+/Mn2+ dependent 1B regulates the hematopoietic stem cell homeostasis via the Wnt/b- catenin signaling
Zhiyuan Lu,1,2,3* Hanzhi Yu,4* Yanxia Li,1,2 Guangsen Xu,1,2 Xiaoxun Li,1,2 Yongjun Liu,1,2 Yuemao Shen,1,2 Zhigang Cai4 and Baobing Zhao1,2,5
1Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan; 2NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan; 3School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan; 4The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Pharmacology, School of Basic Medical Science, Tianjin Medical University, Tianjin and 5Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
*ZL and HY contributed equally as first authors.
Abstract
Hematopoietic stem cells (HSC) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal ca- pacity and long-term maintenance. How HSC 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 HSC 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 common lymphoid progenitors. 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 HSC revealed the disruptive quiescence of HSC. Mechanistically, Ppm1b interacted with b-cat- enin and mediated its dephosphorylation. Loss of Ppm1b led to the decrease in the active b-catenin (non-phosphorylated) that interrupted the Wnt/b-catenin signaling in HSC, which consequently suppressed HSC expansion. Together, our study identified an indispensable role for Ppm1b in regulating HSC homeostasis via the Wnt/b-catenin pathway.
Introduction
Hematopoietic stem cells (HSC) have the potential for both self-renewal and multipotent differentiation into all blood cell lineages during the lifespan.1 They are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance, which is responsible for maintaining and rebuilding hematopoi- esis.2,3 Functional HSC homeostasis is tightly regulated by multiple factors including cell cycle-associated factors and cell metabolism. Intrinsic programs, cell-autonomous and extrinsic signals from the microenvironment comprise a complicated network, which preserves the balance between
activation and quiescence in HSC.4,5
The reversible phosphorylation of protein regulated by ki- nase and phosphatase is one of the main post-translational modifications that is involved in an extremely wide range of intracellular processes including metabolism, cell death, cell proliferation and differentiation.6,7 Recent studies have demonstrated that protein kinase plays a crucial role in the functional regulation of HSC, such as receptor tyrosine kinases (FLT3,8 c-KIT,9 and TIE210), glycogen synthase kinase 3b,11 sphingosine kinase 2,12 and Janus kinase 2.13 Despite the equally important biological significance, our understand- ing of protein phosphatases in hematopoietic regeneration still lags behind that of kinases due to their complicated
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Correspondence: Baobing Zhao baobingzh@sdu.edu.cn
Received: Accepted: Early view:
September 18, 2023. January 31, 2024. February 8, 2024.
https://doi.org/10.3324/haematol.2023.284305
©2024 Ferrata Storti Foundation Published under a CC BY-NC license