Dataset Information

Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress.

ABSTRACT: The bone marrow contains distinct cell types that work in coordination to generate blood and immune cells, and it is the primary residence of hematopoietic stem cells (HSCs) and more committed multipotent progenitors (MPPs). Even at homeostasis the bone marrow is a dynamic environment where billions of cells are generated daily to replenish short-lived immune cells and produce the blood factors and cells essential for hemostasis and oxygenation. In response to injury or infection, the marrow rapidly adapts to produce specific cell types that are in high demand revealing key insight to the inflammatory nature of "demand-adapted" hematopoiesis. Here we focus on the role that resident and monocyte-derived macrophages play in driving these hematopoietic programs and how macrophages impact HSCs and downstream MPPs. Macrophages are exquisite sensors of inflammation and possess the capacity to adapt to the environment, both promoting and restraining inflammation. Thus, macrophages hold great potential for manipulating hematopoietic output and as potential therapeutic targets in a variety of disease states where macrophage dysfunction contributes to or is necessary for disease. We highlight essential features of bone marrow macrophages and discuss open questions regarding macrophage function, their role in orchestrating demand-adapted hematopoiesis, and mechanisms whereby they regulate HSC function.

SUBMITTER: Seyfried AN

PROVIDER: S-EPMC7396643 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress.

Seyfried Allison N AN Maloney Jackson M JM MacNamara Katherine C KC

Frontiers in immunology 20200723

The bone marrow contains distinct cell types that work in coordination to generate blood and immune cells, and it is the primary residence of hematopoietic stem cells (HSCs) and more committed multipotent progenitors (MPPs). Even at homeostasis the bone marrow is a dynamic environment where billions of cells are generated daily to replenish short-lived immune cells and produce the blood factors and cells essential for hemostasis and oxygenation. In response to injury or infection, the marrow rap ...[more]

PMID: 32849512

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Project description: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.

Dataset Information

Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress.

Publications

Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress.

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