Heterogeneity of high-potency multilineage hematopoietic stem cells and identification of “Super” transplantability
Abstract
Abstract Hematopoietic stem cells (HSCs) are heterogeneous, and the quality of HSCs—that is, transplantability—is a key determinant for posttransplant hematopoietic reconstitution. However, molecular modalities of high-potency HSCs with superior transplantability still remain poorly understood. Here, we conducted large-scale single-clone serial-transplant experiments and tracked descendant cells of 288 HSC clones to quantify their intrinsic capability for hematopoietic reconstitution. Using integrated single-cell transcriptional, immunophenotypical, and Bayesian dynamic analyses, we uncovered 3 classes of HSC clones (“Super,” “Flash,” and “Trickle”) that had higher output in the first generation but exhibited markedly different behavior in later generations. The Super-class HSC clones comprised 4% of the HSCs and manifested persistent superior transplantability and balanced myeloid/lymphoid–lineage outputs across generations in serial transplants. The Super-class HSCs had a unique molecular signature, including low expression of CD27, that was distinct from previously known classical HSC signatures. Validation experiments indicated that CD27– HSCs had superior transplantability compared with CD27+ HSCs. Our study asserted an operational definition for Super transplantability of HSCs, defined its molecular program, and suggested new directions for enriching high-potency HSCs in grafts.
Article Details
Authors (25)
Fang Dong
Sen Zhang
Caiying Zhu
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Zining Yang
1State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Lisha Wang
Michigan Center for Translational Pathology, University of Michigan
Yao Ma
Department of Chemistry and Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, China
Jiayi Lu
Materials Genome Institute
Xialin Li
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Xiaofang Wang
Nini Wang
Shanshan Zhang
Miner Xie
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Jinhong Wang
Transmissible Cancer Group, Department of Veterinary Medicine, University of Cambridge
Xiaobing Zhang
Yawei Zheng
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Shihui Ma
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Hideo Ema
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Hui Cheng
Sha Hao
1National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
Toshio Suda
Yu Lan
Bing Liu
Ping Zhu
Junren Chen
Tao Cheng
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Jiangsu Key Laboratory of Advanced Negative Carbon Technologies