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Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis
- Source :
- Blood. 114:4064-4076
- Publication Year :
- 2009
- Publisher :
- American Society of Hematology, 2009.
-
Abstract
- Severe sepsis is one of the leading causes of death worldwide. High mortality rates in sepsis are frequently associated with neutropenia. Despite the central role of neutrophils in innate immunity, the mechanisms causing neutropenia during sepsis remain elusive. Here, we show that neutropenia is caused in part by apoptosis and is sustained by a block of hematopoietic stem cell (HSC) differentiation. Using a sepsis murine model, we found that the human opportunistic bacterial pathogen Pseudomonas aeruginosa caused neutrophil depletion and expansion of the HSC pool in the bone marrow. “Septic” HSCs were significantly impaired in competitive repopulation assays and defective in generating common myeloid progenitors and granulocyte-monocyte progenitors, resulting in lower rates of myeloid differentiation in vitro and in vivo. Delayed myeloid-neutrophil differentiation was further mapped using a lysozyme–green fluorescent protein (GFP) reporter mouse. Pseudomonas's lipopolysaccharide was necessary and sufficient to induce myelosuppresion and required intact TLR4 signaling. Our results establish a previously unrecognized link between HSC regulation and host response in severe sepsis and demonstrate a novel role for TLR4.
- Subjects :
- Lipopolysaccharides
Male
Neutropenia
Myeloid
Hematopoiesis and Stem Cells
Cellular differentiation
Immunology
Apoptosis
Mice, Transgenic
Biology
Biochemistry
Sepsis
Mice
medicine
Animals
Humans
Myeloid Cells
Pseudomonas Infections
Progenitor cell
Mice, Inbred C3H
Multipotent Stem Cells
Hematopoietic stem cell
Cell Differentiation
Cell Biology
Hematology
Hematopoietic Stem Cells
medicine.disease
Hematopoiesis
Mice, Inbred C57BL
Toll-Like Receptor 4
Disease Models, Animal
Haematopoiesis
medicine.anatomical_structure
Female
Bone marrow
Stem cell
Signal Transduction
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 114
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....131c54191d2390a03e6f7b16e3f26511