Heterogeneity of high-potency multilineage hematopoietic stem cells and identification of “Super” transplantability
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.
Authors
- Jiayi Lu (ORCID: https://orcid.org/0000-0001-9680-5716)
- Yawei Zheng (ORCID: https://orcid.org/0000-0003-2497-7353)
- Sha Hao (ORCID: https://orcid.org/0000-0002-2403-0840)
- Zining Yang (ORCID: https://orcid.org/0000-0002-6176-5715)
- Junren Chen (ORCID: https://orcid.org/0000-0003-3691-4931)
- Xialin Li (ORCID: https://orcid.org/0000-0002-9955-5465)
- N. Wang
- Yao Ma (ORCID: https://orcid.org/0000-0003-0815-7910)
- Toshio Suda (ORCID: https://orcid.org/0000-0001-7540-1771)
- Hideo Ema (ORCID: https://orcid.org/0000-0001-9939-457X)
- Hui Cheng (ORCID: https://orcid.org/0000-0001-9154-9282)
- Ping Zhu (ORCID: https://orcid.org/0000-0002-4521-7524)
- Miner Xie (ORCID: https://orcid.org/0009-0003-2790-4616)
- Bing Liu (ORCID: https://orcid.org/0000-0002-7313-6924)
- Sen Zhang (ORCID: https://orcid.org/0000-0003-3849-6817)
- Xiao‐Bing Zhang (ORCID: https://orcid.org/0000-0003-4319-6181)
- Shanshan Zhang (ORCID: https://orcid.org/0000-0002-7138-9469)
- Xiaofang Wang (ORCID: https://orcid.org/0000-0002-7370-7192)
- Lisha Wang (ORCID: https://orcid.org/0000-0002-6482-1073)
- Jinhong Wang
- Lan Yu (ORCID: https://orcid.org/0000-0002-7087-0883)
- Fang Dong (ORCID: https://orcid.org/0000-0001-5991-0728)
- Tao Cheng (ORCID: https://orcid.org/0000-0003-4395-1095)
- Caiying Zhu
- Shihui Ma
Institutions
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Academy of Military Medical Sciences (CN)
- Chinese PLA General Hospital (CN)
- Institute of Hematology & Blood Diseases Hospital (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Blood
- Published
- 2025-04-21
- DOI
- https://doi.org/10.1182/blood.2024027872
- Citations
- 7
- Primary Topic
- Hematopoietic Stem Cell Transplantation
- Type
- article
- Field-Weighted Citation Impact
- 12.39
Funders
- National Natural Science Foundation of China
- Science Fund for Creative Research Groups
- Chinese Academy of Medical Sciences
- Tianjin Science and Technology Committee