Figure: HSC niches in bone marrow control HSC homeostasis and lymphopoiesis. MSPCs, together with some sinusoidal endothelial cells, express soluble and membrane-bound SCF, CXCL12, and IL-7 that not only regulate HSC and MPP numbers but also sustain lymphopoiesis. MSPCs in the bone marrow are mostly perisinusoidal cells that can differentiate into osteoblasts, osteocytes, chondrocytes, and adipocytes. MSPC differentiation is coordinated with the downregulation of SCF, CXCL12, and IL-7 expression.
Video: ProB and PreB cell movement within bone marrow visualized by intravital 2-photon microscopy. Differences in the dynamic behavior between proB and preB cells enables switching from constitutively high to intermittently low IL-7 receptor signaling in vivo.
Figure: Interactions between Gαi protein-coupled receptors and BCR signaling. Left, Indirect regulation of BCR signaling through cAMP. Activation of Gαi proteins by chemoattractant sensing may inhibit adenylyl cyclase (AC) activity counteracting the effects of Gαs-coupled receptors and thus lower cytoplasmic concentration of the secondary messenger cAMP. In turn, by yet unidentified mechanisms, cAMP may inhibit BCR signaling. Right, Interaction between heterotrimeric G proteins and components of the BCR signal transduction pathway (i.e., Cdc42 and RAC proteins).
Metabolic requirements of developing B cells and B cell leukemias
B cell progenitors undergo massive rounds of cell division mostly during two discrete developmental windows. We are interested in identifying the nutrients and studying the mechanisms that enable progenitor cells to produce large numbers of daughter cells. We are also very interested in uncovering similarities and differences between normal and leukemic B-lineage cells. This project is open to trainees interested in joining our lab (Join Us).
Bone marrow Stem Cell niches
All blood cells develop from hematopoietic stem cells (HSC) through complex developmental transitions that require cell-lineage instructive transcription factors and cell-extrinsic lineage-instructive cytokines. Stem cell niches are key organizers of HSC maintenance and differentiation due to their capacity to produce cytokines (e.g. Stem Cell Factor, IL-7, IL-15, etc.) and chemokines (e.g. CXCL12). Stem cell niches are formed predominantly by a relatively rare population of mesenchymal stem/progenitor cells (MSPCs) that expresses Leptin receptor and PDGFRs. Importantly, MSPCs either reduce or loose the ability to express niche cytokines upon differentiation into mesenchymal-lineage cells such as adipocytes, osteoblasts, chondrocytes. These observations suggest that cytokine production by MSPCs is regulated by short and/or long-range signals, but these mechanisms are largely unknown. Also poorly understood is the physiological role of MSPCs in the long-term maintenance of antibody-secreting plasma cells.
Where and how B cell development occurs in vivo.
B cell precursors switch from non-motile and highly adherent states (proB cell stage) to highly motile and less adherent states (preB cell stage). As a consequence, the time these two distinct B cell subsets spend in contact with IL-7 producing MSPCs is remarkably different and highly regulated. This type of change in dynamic behavior suggests that cross-talk between proB, preB, and MSPCs is important for the quality and possibly quantity of B cells being produced. This is a highly exciting area of research that is likely to have a major impact in our understanding of how pre-leukemic and leukemic B cell progenitors change the bone marrow microenvironment.
Chemoattractants, receptors, and B cell homeostasis.
Immune cells are highly organized in primary and secondary lymphoid organs. B cells and T cells occupy distinct areas of the spleen and lymph nodes due to the differential expression of chemoattractant receptors. Chemoattractants act as ZIP codes for immune cells to know where they should be located. However, chemoattractant receptor signaling does more to cells than simply inform them of where they are or where they should go. By taking advantage of one of nature’s tools, Pertussis toxin, we are currently investigating the physiological impact of blocked chemoattractant receptor signaling in the development and maintenance of B cells.