Guangyu Zhang
Yandong Gong
Xiaowei Ning
Zhijie Bai
Jian He
Fan Zhou
Yanli Ni
Yu Lan
Bing Liu
aState Key Laboratory of Proteomics, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, 100071, China
bBeijing Advanced Innovation Center for Genomics, Department of Obstetrics and Gynecology, Third Hospital, School of Life Sciences, Peking University, Beijing, China
cBiomedical Pioneering Innovation Center and Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China
dState Key Laboratory of Experimental Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China
eGuangzhou Regenerative Medicine and Health-Guangdong Laboratory (GRMH-GDL); Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510632, China
fState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, 300020, China
More InformationCorresponding author: E-mail address: rainyblue_1999@126.com (Yu Lan);E-mail address: bingliu17@yahoo.com (Bing Liu)
Received Date: 2019-09-03
Accepted Date:2019-10-11
Rev Recd Date:2019-09-27
Available Online: 2019-11-04 Publish Date:2019-10-20
Abstract
Abstract
The functional heterogeneity of hematopoietic stem cells (HSCs) has been comprehensively investigated by single-cell transplantation assay. However, the heterogeneity regarding their physiological contribution remains an open question, especially for those with life-long hematopoietic fate of rigorous self-renewing and balanced differentiation capacities. In this study, we revealed that Procr expression was detected principally in phenotypical vascular endothelium co-expressing Dll4 and CD44 in the mid-gestation mouse embryos, and could enrich all the HSCs of the embryonic day 11.5 (E11.5) aorta-gonad-mesonephros (AGM) region. We then used a temporally restricted genetic tracing strategy to irreversibly label the Procr-expressing cells at E9.5. Interestingly, most labeled mature HSCs in multiple sites (such as AGM) around E11.5 were functionally categorized as lymphomyeloid-balanced HSCs assessed by direct transplantation. Furthermore, the labeled cells contributed to an average of 7.8% of immunophenotypically defined HSCs in E14.5 fetal liver (FL) and 6.9% of leukocytes in peripheral blood (PB) during one-year follow-up. Surprisingly, in aged mice of 24 months, the embryonically tagged cells displayed constant contribution to leukocytes with no bias to myeloid or lymphoid lineages. Altogether, we demonstrated, for the first time, the existence of a subtype of physiologically long-lived balanced HSCs as hypothesized, whose precise embryonic origin and molecular identity await further characterization.Keywords: Genetic lineage tracing,
Hematopoietic stem cells,
Heterogeneity,
Aorta-gonad-mesonephros region
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