Heterogeneity of high-potency multilineage hematopoietic stem cells and identification of “Super” transplantability
Fang Dong, Sen Zhang, Caiying Zhu, Zining Yang, Lisha Wang, Yao Ma, Jiayi Lu, Xialin Li, Xiaofang Wang, Nini Wang, Shanshan Zhang, Miner Xie, Jinhong Wang, Xiao‐Bing Zhang, Yawei Zheng, Shihui Ma, Hideo Ema, Hui Cheng, Sha Hao, Toshio Suda, Lan Yu, Bing Liu, Ping Zhu, Junren Chen, Tao Cheng
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.