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Research Article
He Huang
First Hospital of Zhejiang Province: Zhejiang University School of Medicine First Affiliated Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2723-1621
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Hematopoietic stem cell (HSC) aging, which is accompanied by loss of self-renewal capacity, myeloid-biased differentiation and increased risks of hematopoietic malignancies, is an important focus in stem cell research. However, the mechanisms underlying HSC aging have not been fully elucidated. In the present study, we integrated 3 independent single-cell transcriptome datasets of HSCs together and identified Il10ra and Tnfsf14 as two markers of inflammatory and apoptosis-biased aged HSCs. Besides, common differentially expressed genes (DEGs) between young and aged HSCs were identified and further validated by quantitative RT-PCR. Functional enrichment analysis revealed that these DEGs were predominantly involved in the cell cycle and the tumor necrosis factor (TNF) signaling pathway. We further found that the Skp2-induced signaling pathway (Skp2→Cip1→CycA/CDK2→DP-1) contributed to a rapid transition through G1 phase in aged HSCs. In addition, analysis of the extrinsic alterations on HSC aging revealed the increased expression levels of inflammation genes in bone marrow microenvironment. Colony formation unit assays showed that inflammatory cytokines promoted cellular senescence and that blockade of inflammatory pathway markedly rejuvenated aged HSC functions and increased B cell output. Collectively, our study elucidated the biological characteristics of HSC aging, and the genes and pathways we identified could be potential biomarkers and targets for the identification and rejuvenation of aged HSCs.
Keywords
Hematopoietic stem cells, Aging, Single cell integrated analysis, Cell cycle, Inflammation
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This is a list of supplementary files associated with this preprint. Click to download.
- SupplementaryFigure1.tif
(A) Circle plot of the cell-cell communication network showing that the inflammatory pathway network (OSM, IL16 and IL10 signaling pathways) became more complex and interconnected in the aged bone marrow niche. (B) Relative contribution of each ligand-receptor pair to the overall communication network of the IL2, CCL and complement signaling pathways.
- SupplementaryTable1.docx
- SupplementaryTable2.docx
- SupplementaryTable3.docx
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research Article
He Huang
First Hospital of Zhejiang Province: Zhejiang University School of Medicine First Affiliated Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2723-1621
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 25 May, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Translational Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Hematopoietic stem cell (HSC) aging, which is accompanied by loss of self-renewal capacity, myeloid-biased differentiation and increased risks of hematopoietic malignancies, is an important focus in stem cell research. However, the mechanisms underlying HSC aging have not been fully elucidated. In the present study, we integrated 3 independent single-cell transcriptome datasets of HSCs together and identified Il10ra and Tnfsf14 as two markers of inflammatory and apoptosis-biased aged HSCs. Besides, common differentially expressed genes (DEGs) between young and aged HSCs were identified and further validated by quantitative RT-PCR. Functional enrichment analysis revealed that these DEGs were predominantly involved in the cell cycle and the tumor necrosis factor (TNF) signaling pathway. We further found that the Skp2-induced signaling pathway (Skp2→Cip1→CycA/CDK2→DP-1) contributed to a rapid transition through G1 phase in aged HSCs. In addition, analysis of the extrinsic alterations on HSC aging revealed the increased expression levels of inflammation genes in bone marrow microenvironment. Colony formation unit assays showed that inflammatory cytokines promoted cellular senescence and that blockade of inflammatory pathway markedly rejuvenated aged HSC functions and increased B cell output. Collectively, our study elucidated the biological characteristics of HSC aging, and the genes and pathways we identified could be potential biomarkers and targets for the identification and rejuvenation of aged HSCs.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
- SupplementaryFigure1.tif
(A) Circle plot of the cell-cell communication network showing that the inflammatory pathway network (OSM, IL16 and IL10 signaling pathways) became more complex and interconnected in the aged bone marrow niche. (B) Relative contribution of each ligand-receptor pair to the overall communication network of the IL2, CCL and complement signaling pathways.
- SupplementaryTable1.docx
- SupplementaryTable2.docx
- SupplementaryTable3.docx
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