In the Schuettpelz Lab, we are interested in understanding how inflammatory signals regulate hematopoietic stem cells (HSCs), which are rare, multipotent adult stem cells that give rise to all of the different types of blood cells.
Lab Focus 1: The regulation of normal and premalignant HSCs by TLR signaling. Toll like receptors (TLRs) are a family of pattern recognition receptors that play a central role in pathogen recognition and the innate immune response. While they have long been known to regulate effector immune cells, recent studies have demonstrated the TLRs may regulate the immune response from the level of the HSC. Exposure to TLR agonists has been shown to stimulate HSC cycling and skew HSC differentiation toward the myeloid lineage. In addition, chronic TLR signaling has been shown to impair HSC function. We are currently using mouse models to assess the role of individual TLRs in the regulation of HSCs, and are characterizing the cell-autonomous versus non-autonomous effects of TLR signaling on HSCs through the use of chimeric mice and mice with conditional loss of TLR expression. Notably, the expression of TLRs, particularly TLR2, is markedly increased on the HSCs of patients with myelodysplastic syndromes (MDS), a group of HSC disorders characterized by ineffective hematopoiesis and a high risk of transformation to acute leukemia. Given that TLRs regulate HSC proliferation, differentiation and function, we hypothesize that enhanced TLR signaling contributes to the ineffective hematopoiesis and/or leukemic transformation in MDS. We are currently augmenting or reducing TLR signaling in mouse models of MDS and testing the effects on HSC function and disease progression, with the ultimate goal of targeting this pathway therapeutically for the treatment of patients with MDS.
Lab Focus 2: Role of tetraspanins in hematopoiesis. Tetraspanins are a family of transmembrane proteins that are important for organizing the plasma membrane and regulating processes such as cellular migration, adhesion and activation. Loss of the tetraspanin family member CD53 is associated with recurrent infections in humans, however its role in hematopoiesis and the immune system is not well understood. We found that expression of CD53 is markedly upregulated upon mobilization of HSCs, and have determined that CD53 is necessary for preserving the function of mobilized HSCs. In addition, using a CD53-/- knockout mouse, we have identified a critical role for CD53 in B cell development. Ongoing experiments are aimed at defining the role of CD53 in both HSCs and B cells. Furthermore, high levels of CD53 have been found on malignant B cells, and we are therefore investigating CD53 as a potential therapeutic target in B-lineage malignancies
Work in our laboratory is supported by the National Institutes of Health (NHLBI), The Children's Discovery Institute, Alex's Lemonade Stand Foundation, Hyundai Hope on Wheels and the St. Baldrick’s Foundation.