Functional heterogeneity of mouse fetal liver hematopoietic stem cells revealed by clonal lineage tracing and single-cell transcriptomics
5 affiliations
- 1State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Senior Department of Hematology, Chinese PLA General Hospital, Beijing 100071, China
- 2Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing 100053, China
- 3State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
- 4Tianjin Institutes of Health Science, Tianjin 301600, China
- 5Department of Medical Genetics, College of Basic Medical Science, Army Medical University (Third Military Medical University), Chongqing 400038, China
Abstract
The relationship between lineage output and transcriptional features of hematopoietic stem cells (HSCs) has been reported in adult bone marrow, yet it remains unclear in fetal liver, given their distinct developmental stage and microenvironment. Here, we systematically characterized the functions of E14.5 mouse fetal liver HSCs by lentiviral barcode labeling followed by transplantation, with subsequent single-cell RNA sequencing (scRNA-seq) and clonal analysis performed on donor-derived HSCs and their progeny in recipient bone marrow. We identified three HSC subtypes based on lineage bias, with myeloid-biased and balanced subtypes predominating. Importantly, within the same subtype, HSCs and their progeny share several transcriptional programs, and these programs show minimal overlap between subtypes. We term the retention of subtype-specific transcriptional features across lineages as “transcriptional persistence”. Notably, this phenomenon was not observed in adult bone marrow. Alternatively, classification by progeny output activity revealed the presence of low-output and high-output subtypes within fetal liver HSCs. Although these two subtypes showed no significant difference in stemness features, they exhibited distinct transcriptional features and signaling activation states, which also differed from their counterparts in bone marrow, indicating that the biological characteristics of HSCs with different output activities vary by developmental stage. Of note, in both fetal liver and adult bone marrow, transcriptional persistence showed no obvious correlation with output activity, suggesting a specific coupling relationship between transcriptional persistence and lineage bias. Collectively, our study provides a clonal-resolution view of fetal liver HSC heterogeneity, enhancing our understanding of HSC diversity across different developmental stages.
Related
- Single-cell transcriptomics-based analysis of cellular heterogeneity in aggrephagy in gastric cancer and development of a prognostic model
- Mapping intestinal microenvironment heterogeneity in Hirschsprung's disease by spatial transcriptomics: Role of THBS1 in macrophage polarization and neural stem cell regulation.
- Single-cell analysis reveals temporal heterogeneity of neutrophil-lineage states after spinal cord injury
- Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics
- Spatial Transcriptomics Reveals HER2/AR-Associated Heterogeneity and Alternative Surface Targets in Salivary Duct Carcinoma
BibTeX
@article{zhang2026functional,
title = {{Functional heterogeneity of mouse fetal liver hematopoietic stem cells revealed by clonal lineage tracing and single-cell transcriptomics}},
author = {Man Zhang and Yanli Ni and Di Liu and Dong Xiang and Gaoke Liu and Jie Zhou and Yu Lan and Bing Liu and Zongcheng Li},
journal = {Zoological Research},
year = {2026},
month = sep,
doi = {10.24272/j.issn.2095-8137.2026.321},
url = {https://doi.org/10.24272/j.issn.2095-8137.2026.321},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Functional heterogeneity of mouse fetal liver hematopoietic stem cells revealed by clonal lineage tracing and single-cell transcriptomics
AU - Man Zhang
AU - Yanli Ni
AU - Di Liu
AU - Dong Xiang
AU - Gaoke Liu
AU - Jie Zhou
AU - Yu Lan
AU - Bing Liu
AU - Zongcheng Li
PY - 2026
DA - 2026/09/18
JO - Zoological Research
DO - 10.24272/j.issn.2095-8137.2026.321
UR - https://doi.org/10.24272/j.issn.2095-8137.2026.321
AB - The relationship between lineage output and transcriptional features of hematopoietic stem cells (HSCs) has been reported in adult bone marrow, yet it remains unclear in fetal liver, given their distinct developmental stage and microenvironment. Here, we systematically characterized the functions of E14.5 mouse fetal liver HSCs by lentiviral barcode labeling followed by transplantation, with subsequent single-cell RNA sequencing (scRNA-seq) and clonal analysis performed on donor-derived HSCs and their progeny in recipient bone marrow. We identified three HSC subtypes based on lineage bias, with myeloid-biased and balanced subtypes predominating. Importantly, within the same subtype, HSCs and their progeny share several transcriptional programs, and these programs show minimal overlap between subtypes. We term the retention of subtype-specific transcriptional features across lineages as “transcriptional persistence”. Notably, this phenomenon was not observed in adult bone marrow. Alternatively, classification by progeny output activity revealed the presence of low-output and high-output subtypes within fetal liver HSCs. Although these two subtypes showed no significant difference in stemness features, they exhibited distinct transcriptional features and signaling activation states, which also differed from their counterparts in bone marrow, indicating that the biological characteristics of HSCs with different output activities vary by developmental stage. Of note, in both fetal liver and adult bone marrow, transcriptional persistence showed no obvious correlation with output activity, suggesting a specific coupling relationship between transcriptional persistence and lineage bias. Collectively, our study provides a clonal-resolution view of fetal liver HSC heterogeneity, enhancing our understanding of HSC diversity across different developmental stages.
SN - 2095-8137
ER -