Abstract
BackgroundDuring aging, hematopoietic stem cells (HSC) lose progressively both their self-renewal and differentiation potential. The precise molecular mechanisms of this phenomenon are not well established. To uncover the molecular events underlying this event, we have performed a bioinformatics analysis of 650 single-cell transcriptomes.MethodsSingle-cell transcriptome analyses of expression heterogeneity, cell cycle, and cell trajectory in human cell compartment enriched in hematopoietic stem cell compartment were investigated in the bone marrow according to the age of the donors. Identification of aging-related nodules was identified by weighted correlation network analysis in this primitive compartment.ResultsThe analysis of single-cell transcriptomes allowed to uncover a major upregulation of EGR1 in human-aged lineage−CD34+CD38− cells which present cell cycle dysregulation with reduction of G2/M phase according to less expression of CCND2 during S phase. EGR1 upregulation in aging hematopoietic stem cells was found to be independent of cell cycle phases and gender. EGR1 expression trajectory in aged HSC highlighted a signature enriched in hematopoietic and immune disorders with the best induction of AP-1 complex and quiescence regulators such as EGR1, BTG2, JUNB, and NR41A. Sonic Hedgehog-related TMEM107 transmembrane molecule followed also EGR1 cell trajectory. EGR1-dependent gene weighted network analysis in human HSC-associated IER2 target protein-specific regulators of PP2A activity, IL1B, TNFSF10 ligands, and CD69, SELP membrane molecules in old HSC module with immune and leukemogenic signature. In contrast, for young HSC which were found with different cell cycle phase progression, its specific module highlighted upregulation of HIF1A hypoxic factor, PDE4B immune marker, DRAK2 (STK17B) T cell apoptosis regulator, and MYADM myeloid-associated marker.ConclusionEGR1 was found to be connected to the aging of human HSC and highlighted a specific cell trajectory contributing to the dysregulation of an inflammatory and leukemia-related transcriptional program in aged human HSCs. EGR1 and its program were found to be connected to the aging of human HSC with dissociation of quiescence property and cell cycle phase progression in this primitive hematopoietic compartment.
Highlights
During aging, hematopoietic stem cells (HSC) lose progressively both their self-renewal and differentiation potential
Cell cycle analysis revealed that Early growth response 1 (EGR1), cyclin-dependent kinase 6 (CDK6), and CDK4 regulations of transcripts were found independent of phase characterization (Fig. 1i)
Among D-type cyclins, Cyclin D2 (CCND2), the best expressed one in HSC, was found less positive in S phase of old HSC. These results suggest that old human HSC are characterized by deregulation of CDK4/6/D-type cyclin CCND2 complex and harbored an increased expression of an EGR1 transcription factor
Summary
Hematopoietic stem cells (HSC) lose progressively both their self-renewal and differentiation potential. The hematopoietic organ is mainly composed of hematopoietic cells and their niche is principally localized in the bone marrow Some cytokines such as interleukin 1-beta in the bone marrow microenvironment are known to contribute to the aging process in the hematopoietic stem cell (HSC) compartment [2]. The aged bone marrow has a reduced capability of retaining HSCs in their niche with increased hematopoietic stem cell mobilization [3]. Hematopoietic stem cells exhibit age-related changes that include impaired adherence to stromal cells, and in some strains of mice [5] as well as in elderly humans, quantitative and qualitative changes with a myeloid bias in terms of their differentiation potential [6]. The number of hematopoietic stem cells is found to be increased in the bone marrow with the age in some strains of mice [11]
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