Stress-induced Activation of Hematopoietic Stem Cells

HI-STEM Junior Research Group Stress-induced Activation of Hematopoietic Stem Cells

Dr. Marieke Essers

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Infection is a major source of natural stress for the hematopoietic system, leading to the exhaustion of large amounts of blood and immune cells. Restoration of homeostasis following successful elimination of the infection depends on the replacement of these cells by hematopoietic stem cells (HSCs). In response to infection, long term quiescent HSCs are efficiently recruited into the cell cycle and returned back to quiescence after re-establishment of homeostasis. We have previously demonstrated that IFN, produced by virally infected immune cells to block the infection of more mature blood cells, can directly activate the entire HSC pool (Essers et al, 2009, Nature). The focus of our current research is to understand the link of inflammation and the HSC compartment via the effect of the pro-inflammatory cytokines on quiescent HSCs.

Even though HSCs directly respond to cytokines like IFNs, it remains unclear whether HSCs can directly sense the infectious state. HSCs have the machinery to detect infectious particles as they express most of the Toll like receptors (TLRs), the major receptors for detecting pathogen-associated molecular patterns (PAMPs), on their surface. We investigate how HSCs as well as their niche environment in the bone marrow respond to different inflammatory cytokines, pathogens, and viruses. Infections are for example associated with extensive platelet consumption. We have now identified potent stem-like megakaryocyte-committed progenitors (SL-MkPs) within the HSC compartment. Acute IFN signaling triggers cell cycle activation of quiescent SL-MkP and Mk protein production, mediating an efficient platelet recovery after inflammation-induced thrombocytopenia (Haas et al, 2015, Cell Stem Cell).

FUTURE OUTLOOK:
A better understanding on how quiescent HSCs can be activated by pro-inflammatory cytokines might open up possibilities to target quiescent leukemic stem cells (LSCs), making them susceptible to conventional chemotherapy. LSCs are thought to initiate and maintain leukemia. They can also transplant the disease and show unlimited self-renewal activity. Furthermore, LSCs appear to be resistant to conventional therapies including chemotherapy. Their quiescent status as well as localization in protective stem cell niches, are likely critical components. Thus, our finding that IFN? activates normal quiescent HSCs by putatively altering their niche interactions, may open new possibilities for combining IFN? with classical chemotherapy to target LSCs and potentially cure the disease.

Contact

Dr. Marieke Essers
Stress-induced Activation of Hematopoietic Stem Cells (A011)

Deutsches Krebsforschungszentrum und Heidelberg Institut für Stammzelltechnologie und experimentelle Medizin (HI-STEM GmbH)
Im Neuenheimer Feld 280
69120 Heidelberg

Tel.: +49 6221 42 3919
E-Mail: m.essers@dkfz.de

Selected Publications

  • Glauche I. et al. (2012). Therapy of chronic myeloid leukaemia can benefit from the activation of stem cells: simulation studies of different treatment combinations. Br J Cancer. 106, 1742–1752.
  • Essers M.A. et al. (2010). Targeting leukemic stem cells by breaking their dormancy. Mol Oncol., 4, 443–450.
  • Trumpp A. et al. (2010). Awakening dormant haematopoietic stem cells. Nat Rev Immunol., 10, 201–209.
  • Essers M.A. et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 458, 904–908.
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