Nucleoplasmic ZNF467 condensates boost hematopoietic stem cell engraftment via ICAM1-mediated mechanical reprogramming
Abstract
Abstract Hematopoietic stem cell (HSC) transplantation is a life-saving therapy for immune deficiencies and hematologic malignancies, but its efficacy is limited by poor engraftment. Therapeutic enhancement of HSC grafts requires deeper insight into the intrinsic determinants of their regenerative capacity. Here, we identify mechanical robustness as a critical feature distinguishing human HSCs from multipotent progenitors (MPPs). Through integrative biomechanical and transcriptomic profiling, we reveal that ZNF467 is a key regulator of HSC mechanical integrity. Loss of ZNF467 disrupts HSC mechanical fitness and abolishes long-term engraftment. Conversely, an engineered phase-separating ZNF467 variant enhanced mechanical strength and engraftment by activating a mechanoresponsive transcriptional program, including upregulation of ICAM1. ICAM1+ hematopoietic stem and progenitor cells exhibit superior biomechanical properties and improved engraftment efficiency. Furthermore, the phase-separation activity of nucleoplasmic ZNF467 (npZNF467) is crucial for its mechanical reprogramming function, and ectopic npZNF467 expression enhances the engraftment capacity of MPPs. Our findings establish biomechanical regulation as an important determinant of stem cell identity and reveal new strategies for engineering stem cells with enhanced regenerative capacity.
Article Details
Authors (18)
Yandan Chen
1Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine and State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
Jinghao Shen
3Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
Zaisheng Lin
5The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Qingwei Ding
1Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine and State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China
Xiashiyao Zhang
7Department of BioHealth Informatics, Indiana University School of Informatics and Computing, Indianapolis, IN
Meng Zhang
Haoxiang Yang
Department of Modern Mechanics, University of Science and Technology of China
Han Yao
State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College
Sheng Liu
Jun Wan
Shize Liu
10Shanghai Luao Bioengineering Technology, Shanghai, China
Xiaopeng Jia
10Shanghai Luao Bioengineering Technology, Shanghai, China
Xiaodong Wang
CAS Key Laboratory of Science and Technology on Applied Catalysis
Uet Yu
11Blood and Marrow Transplantation Center, Shanghai Children's Medical Center, Shanghai Jiao Tong University Medical School, Shanghai, China
Siguo Hao
2Department of Hematology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Muqing Cao
Hongyuan Jiang
Department of Modern Mechanics, University of Science and Technology of China
Bin Guo