Research in this laboratory is focused on several aspects related to B cell biology, a fundamental player of adaptive immunity. B cells develop from hematopoietic stem cells (HSCs) in specialized microenvironments in the bone marrow, named stem cell niches that are also critical for the maintenance and differentiation of HSCs and of hematopoietic multipotent progenitor cells (MPPs). Besides nurturing B cells, HSCs, and MPPs, bone marrow stem cell niches seem also to be important for controlling adaptive immunity. Antibody producing plasma cells and memory T cells travel from sites of activation and differentiation (mostly, secondary lymphoid organs) back to bone marrow stem cell niches for receiving important cytokine signals that enable their long-term survival. Our laboratory is specifically interested in understanding the molecular cross-talk between HSCs, MPPs, B cells, etc. and stem cell niche cells. Our long-term goals are to make impactful discoveries on the basic understanding of immune cell development, differentiation, and regulation, and in this process reveal novel therapeutic targets and/or strategies for treating B cell-mediated autoimmune diseases, malignancies, or immune deficiencies. Work in this laboratory is in frequent interaction with investigators in the Yale Cancer Center and Yale Stem Cell Center.
Specialized Terms: Immunology; Hematopoiesis; B-lymphocyte development; Bone marrow niches; Cell migration
Active areas of research
1- 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.
2- 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.
3- 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.
B-Lymphocytes; Bone Marrow; Hematopoiesis; Hematopoietic Stem Cells; Immune System; Stromal Cells