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

Rodriguez, Sonia, Chora, Angelo, Goumnerov, Boyan, Mumaw, Christen, Goebel, W. Scott, Fernandez, Luis, Baydoun, Hasan, HogenEsch, Harm, Dombkowski, David M., Karlewicz, Carol A., Rice, Susan, Rahme, Laurence G., Carlesso, Nadia·2009·Blood
DOI 10.1182/blood-2009-04-214916
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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.

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Metadata

Authors
Rodriguez, S., Chora, A., Goumnerov, B., Mumaw, C., Goebel, W. S., Fernandez, L., Baydoun, H., HogenEsch, H., Dombkowski, D. M., Karlewicz, C. A., Rice, S., Rahme, L. G., & Carlesso, N.
Affiliations
  • Herman B Wells Center, Indiana University Simon Cancer Center, School of Medicine, Indiana University, Indianapolis;
  • Massachusetts General Hospital, Harvard Medical School, Boston;
  • Department of Comparative Pathobiology, School of Veterinary Medicine, Purdue University, West Lafayette, IN
Venue
Blood
Publisher
American Society of Hematology
Published
2009-11-05
Volume
114
Issue
19
Pages
4064-4076
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood-2009-04-214916
Cited by
135
References
6
Language
en

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CoChat. (2026). Citation check: Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. https://app.cochat.ai/papers/10.1182/blood-2009-04-214916
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Rodriguez, S., Chora, A., Goumnerov, B., Mumaw, C., Goebel, W. S., Fernandez, L., Baydoun, H., HogenEsch, H., Dombkowski, D. M., Karlewicz, C. A., Rice, S., Rahme, L. G., & Carlesso, N. (2009). Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. Blood. https://doi.org/10.1182/blood-2009-04-214916