Hematopoietic stem cells (HSCs) are rare, multipotent cells that give rise to all of the different types of blood cells. They are quiescent, dividing very infrequently, and have the ability to self-renew, or to generate more stem cells. HSCs reside largely within specialized niches in the bone marrow, where they receive signals from surrounding cells to maintain these fundamental properties of quiescence and self-renewal. The maintenance of these properties is important, as dysregulation of HSCs can lead to disorders of hematopoiesis such as bone marrow failure and leukemia.
While HSCs are largely quiescent, during times of infection or other stresses they are induced to proliferate and differentiate, giving rise to the various effector cells necessary to fight infection. This process is thought to result, in part, in response to a depletion of effector cells as they are recruited away from the bone marrow to the sites of insult. In addition, however, it is becoming increasingly clear that inflammatory cytokines- and even pathogens themselves- may influence the immune response at the level of the stem cell. HSCs express receptors for various inflammatory cytokines and pathogen-associated ligands, and may proliferate and differentiate in response to these signals. While this is probably important in the short-term for the production of an appropriate immune response, chronic exposure to inflammatory signals has been shown to impair HSCs and lead to aberrant HSC cycling, differentiation and loss of repopulating activity (King, et al Nature Rev Immunol 2011; Schuettpelz and Link, Frontiers in Immunology 2013).
The Schuettpelz Lab is interested in understanding how inflammatory signals regulate HSCs. In particular, we are studying the role of toll-like receptor (TLR) signaling in HSCs. TLRs are a family of pattern-recognition receptors that respond to pathogens and play a central role in the innate immune response. While much of the research on TLRs has focused on more committed effector cell types, recent studies suggest that TLRs may even influence the immune response from the level of the HSC. Both mouse and human HSCs express TLRs (Nagai, et al Immunity 2006; Sioud, et al J Mol Biol 2006), and in vitro exposure to TLR agonists has been shown to stimulate HSC cycling and skew HSC differentiation toward the myeloid lineage. Furthermore, chronic in vivo treatment of mice with the TLR4 agonist LPS leads to increased HSC cycling and expansion, but decreased repopulating activity with myeloid skewing in transplantation assays (Esplin, et al J Immunol 2011). Together, these studies suggest that TLR signaling may shape the immune response from the level of the HSC, regulating the proliferation, differentiation and activity of these cells. Finally, enhanced expression of TLRs and increased TLR signaling is associated with myelodysplastic syndrome (MDS), a stem cell disorder characterized by ineffective hematopoiesis and a high risk of transformation to acute leukemia (Maratheftis, et al Clin Cancer Res 2007; Hoffman, et al Blood 2002; Starczynowki, et al Nature Medicine 2010; Wei, et al Leukemia 2013).
Our lab is currently using mouse models to better define the role of individual TLRs in regulating HSC function. In addition, we are exploring the connection between enhanced TLR signaling and MDS through the use of various mouse models of this disease. Furthermore, since TLRs are largely pathogen receptors, we are exploring the contribution of the commensal gut flora to the regulation of HSCs, as the gut microbiome represents a rich source of TLR ligands and is important for normal immune system development. Ultimately we hope that a better understanding of how inflammation and TLRs regulate HSCs will lead to the clinical application of specific agonists or antagonists to improve HSC function in patients undergoing bone marrow transplantation or suffering from bone marrow failure.
Work in our laboratory is supported by the National Institutes of Health (NHLBI), the Child Health Research Center at Washington University, The Children's Discovery Institute, Alex's Lemonade Stand Foundation and Hyundai Hope on Wheels.
Children’s Discovery Institute
Alex’s Lemonade Stand Foundation
Hyundai Hope on Wheels