Inflammation Mediated Bone Marrow Remodeling

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. This leads to consumption of blood and immune cells due to mobilization of these cells to the site of infection, or by apoptosis as part of the host response to invading pathogens. Restoration of the balance of the hematopoietic system following successful elimination of the infection is a crucial part of the recovery of the body. In addition, both clinical and experimental data indicate that depending on the scale and duration, infection and inflammation can induce hematopoietic dysfunction compromising immune defense mechanisms and possibly contributing to the development of hematologic malignancies.

Restoring the balance of the hematopoietic system depends on the replacement of lost immune cells by the activity of hematopoietic stem cells (HSCs). During the last ten years we and others could show that this so-called emergency hematopoiesis is driven by pro-inflammatory cytokines, who are increasingly produced upon infection or inflammation in the bone marrow and can directly drive the activation of normally quiescent HSCs. An interesting observation from these data is the often opposing impact of these pro-inflammatory cytokines on HSCs in vivo versus in vitro. Whereas in vivo treatment of mice with for example IFNα leads to a strong increase in proliferation of the HSCs, in vitro treatment with IFNα inhibits the HSCs. Furthermore, data from viral infection experiments have shown sustained alterations in the inflammatory cytokine/chemokine profile in the bone marrow weeks after the infection. All these data suggest that interactions of HSCs with their direct environment or signals from this environment are important for a proper response of the HSCs during environmental stress. Research in recent years has focused on unraveling the different components of the HSC stem cell niche. However, the molecular and cellular basis of the BM HSC niche, and signals exchanged between HSC and niche cells under stress conditions remain poorly understood.

We initially focused on how the niche responds to inflammatory stress, and could show that the BM stem cell vascular niche was remodeled in response to IFNα. IFNα treatment of mice resulted in increased BM vascularity, expression of key inflammatory and endothelial-stimulatory markers on ECs and increased BM vascular leakiness. These data indicate a novel acute response of the BM vasculature to primary inflammatory signaling, suggesting alterations of the HSC niche in response to stress. ECs are not the only cells in the BM niche responding to inflammatory stress. Using different mouse models and single cell sequencing technology we are currently not only investigating the impact of inflammatory stress on the other components of the niche but also try to unravel the possible changes in interactions and signals between the HSCs and the niche. One example is our data on the role of the extracellular matrix protein Matrilin-4 (Matn4) in the regulation of the HSC response. Under homeostasis high expression of Matn-4 in HSCs confers a resistance to stress stimuli. In situations of acute stress, such as an infection or transplantation, this protection is rapidly lost through down-regulation of Matn-4, allowing HSCs to efficiently replenish the blood system. Thus, these data indicate an important role for the control of the interactions of HSCs with the extracellular matrix in regulating the HSC stress response in vivo.

In summary, investigating the response of the bone marrow niche and the role of stem cell-ECM-niche interactions in controlling the HSC stress response will help us to better understand the shortterm and longterm impact of infection and inflammation on the HSCs and their niche.

Potential Articles of Interest:

1. Hirche C, Frenz T, Haas S, et al (2017). Systemic Virus Infections differentially modulate Cell Cycle State and Functionality of Long-Term Hematopoietic Stem Cells In Vivo. Cell Reports19: 2345-56

2. Velten L, Haas SF, Raffel S, et al (2017). Human haematopoietic stem cell lineage commitment is a continuous process. Cell Biol.19: 271-281

1. Prendergast AM, Kuck A, van Essen M, et al (2017). IFNa mediated remodeling of endothelial cells in the bone marrow niche. Haematologica,102: 445-453

2. Uckelmann H, Blaszkiewicz S, Nicolae C, et al (2016). Extracellular matrix protein Matrilin-4 regulates stress-induced HSC proliferation via CXCR4. J Exp. Med.213: 1961-1971

3. Haas S, Hansson J, Klimmeck D, et al (2015). Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell17: 422-34