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Transient mechanical activation of the Piezo1 channel facilitates ex vivo expansion of hematopoietic stem cells

Qiwei Wang^1,2,† , Xin Zeng^1,2,† , Haoxiang Yang^3,4,† , Huan Lu^1,2,† , Lingli Jiang^5,† , Lizhen Xu⁶ , Jinxin Li^1,2 , Jingyi Li^1,2 , Yingli Han^1,2 , Xiaoyan Wu⁷ , Yuanhong Zhou⁸ , Xiaolan Chen⁹ , Yanmin Zhao^1,2 , Jimin Shi^1,2 , Yi Luo^1,2 , Fang Ni⁴ , Jie Sun^1,2,7 , Qian Zhao , Fan Yang^1,6 , Peng Xia⁷ , Hongyuan Jiang^3,4,* , He Huang^1,2,* , Pengxu Qian^1,2,*

¹Bone Marrow Transplantation Center of the First Affiliated Hospital and Center for Stem Cell and Regenerative Medicine & Liangzhu Laboratory, Zhejiang University School of Medicine, State Key Laboratory of Experimental Hematology, Hangzhou, Zhejiang, China
²Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China
³Hefei National Laboratory for Physical Science at the Microscale, CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China, Hefei, Anhui, China
⁴Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
⁵Basic Medical Research Center, School of Medicine, Nantong University, Nantong, Jiangsu, China
⁶Department of Biophysics and Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁷Department of Cell Biology and Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁸Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
⁹State Key Laboratory of Chemical Engineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, China
^†These authors contributed equally: Qiwei Wang, Xin Zeng, Haoxiang Yang, Huan Lu, Lingli Jiang
* Correspondence: Hongyuan Jiang(jianghy@ustc.edu.cn)He Huang(huanghe@zju.edu.cn)Pengxu Qian(axu@zju.edu.cn)

Achieving long-term ex vivo expansion of functional hematopoietic stem cells (HSCs) is essential for advancing HSC-based clinical therapies. Although mechanosensitive ion channels are known to play key roles in the hematopoietic system, their involvement in HSC expansion remains unclear. Here, we show that Piezo1 is highly expressed in HSCs. Both genetic deletion and prolonged chemical activation of Piezo1 impair cultured HSC function, indicating that transient mechanical activation of Piezo1 is required for maintenance of HSCs in culture. To achieve this, we screened various microspheres and found that PS500 (500-nm polystyrene microspheres) significantly enhanced ex vivo expansion of mouse bone marrow HSCs with long-term repopulating capacity. PS500 also expanded human umbilical cord blood HSCs capable of engraftment in immunodeficient mice. Mechanistically, PS500 activates Piezo1, triggering Ca2+-dependent expression of proliferative cytokines and subsequent STAT3 activation, which support HSC self-renewal and proliferation. Together, these findings show that PS500 enables transient Piezo1 activation and efficient, non-toxic expansion of functional HSCs, offering a promising approach for the generation of transplantable HSCs for clinical use.

https://doi.org/10.1038/s41422-025-01209-1

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