Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis

Sonia Rodriguez, Angelo Chora, Boyan Goumnerov, Christen Mumaw, W. Goebel, Luis Fernandez, Hasan Baydoun, Harm HogenEsch, David M. Dombkowski, Carol A. Karlewicz, Susan Rice, Laurence G. Rahme, Nadia Carlesso

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 myelo-suppresion 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.

Original languageEnglish
Pages (from-to)4064-4076
Number of pages13
JournalBlood
Volume114
Issue number19
DOIs
StatePublished - Nov 5 2009

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Hematopoietic Stem Cells
Stem cells
Sepsis
Neutropenia
Neutrophils
Pathogens
Muramidase
Green Fluorescent Proteins
Lipopolysaccharides
Assays
Bone
Myeloid Progenitor Cells
Granulocyte Precursor Cells
Apoptosis
Pseudomonas
Innate Immunity
Pseudomonas aeruginosa
Monocytes
Cell Differentiation
Cause of Death

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. / Rodriguez, Sonia; Chora, Angelo; Goumnerov, Boyan; Mumaw, Christen; Goebel, W.; Fernandez, Luis; Baydoun, Hasan; HogenEsch, Harm; Dombkowski, David M.; Karlewicz, Carol A.; Rice, Susan; Rahme, Laurence G.; Carlesso, Nadia.

In: Blood, Vol. 114, No. 19, 05.11.2009, p. 4064-4076.

Research output: Contribution to journalArticle

Rodriguez, S, Chora, A, Goumnerov, B, Mumaw, C, Goebel, W, Fernandez, L, Baydoun, H, HogenEsch, H, Dombkowski, DM, Karlewicz, CA, Rice, S, Rahme, LG & Carlesso, N 2009, 'Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis', Blood, vol. 114, no. 19, pp. 4064-4076. https://doi.org/10.1182/blood-2009-04-214916
Rodriguez, Sonia ; Chora, Angelo ; Goumnerov, Boyan ; Mumaw, Christen ; Goebel, W. ; Fernandez, Luis ; Baydoun, Hasan ; HogenEsch, Harm ; Dombkowski, David M. ; Karlewicz, Carol A. ; Rice, Susan ; Rahme, Laurence G. ; Carlesso, Nadia. / Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. In: Blood. 2009 ; Vol. 114, No. 19. pp. 4064-4076.
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