Stress-induced Activation of Hematopoietic Stem Cells

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

Dr. Marieke Essers

Upon infection, pro-inflammatory cytokines, like IFN?, do not only orchestrate the response of the immune system but also lead to the activation of quiescent HSCs and their BM niche in vivo.
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Infection is a common, natural form of stress, with which the body is regularly challenged. During infection or inflammation, cells of the immune system are responsible for fighting the invading pathogens, leading to high consumption of blood and immune cells. Restoration of the balance of the hematopoietic system following successful elimination of the infection depends on the replacement of lost immune cells by hematopoietic stem cells (HSCs). The focus of our research is to understand the link of inflammation and the hematopoietic stem cell (HSC) compartment via the effect of the pro-inflammatory cytokines on quiescent HSCs and their niche. We have previously demonstrated that the pro-inflammatory cytokine IFN? can directly activate HSCs in vivo (Essers et al, 2009). In our follow-up studies we could show that IFN? induced activation of HSCs mediates efficient recovery of differentiated blood cells (Haas et al, 2015). We identified the stem-like megakaryocyte-committed progenitor (SL-MkP), which is responsible for driving a rapid maturation program, resulting in efficient platelet recovery after inflammation-induced thrombocytopenia (Haas et al, 2015). Using single?cell RNAseq and functional analysis, we could further confirm these findings for the human hematopoietic system (Velten et al, 2017).
Investigating the bone marrow niche under inflammatory stress we could show that the bone marrow stem cell vascular niche was remodeled in response to IFN? (Prendergast et al, 2017), suggesting alterations of the HSC niche in response to stress. Our first data on how the niche plays a role comes from studies on the extracellular matrix protein Matrilin-4, suggesting that high expression of Matrilin-4 in HSCs confers a resistance to stress stimuli. In situations of acute stress, this protection is rapidly lost through down-regulation of Matrilin-4, allowing HSCs to efficiently replenish the blood system (Uckelmann et al, 2016).

FUTURE OUTLOOK
Investigating the effect of stress-induced pro-inflammatory cytokines on HSCs and their niche will further our understanding on the mechanisms by which HSCs are reassuring the successful restoration of the blood system and how are HSCs protected from pathogenic insults. This will help us to better understand the response observed in patients with an intact, but also a compromised immune system, in which infection often lead to a severe disease. In addition, it might also open up possibilities to target quiescent leukemic stem cells (LSCs) for activation, making them susceptible to chemotherapy.

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

  • Velten L. et al. (2017). Human haematopoietic stem cell lineage commitment is a continuous process. Nat. Cell Biol, 19: 271-281.
  • Prendergast A.M. et al. (2017). IFN? mediated remodeling of endothelial cells in the bone marrow niche. Haematologica, 102: 445-453.
  • Uckelmann H. et al. (2016). Extracellular matrix protein Matrilin-4 regulates stress-induced HSC proliferation via CXCR4. J Exp. Med, 213: 1961-197.
  • Haas S. et al. (2015). Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell, 17: 422-34.
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