Dr. Yoshimoto's lab focuses on how innate immune B-1a cells develop in the mouse embryo and how they are maintained in the adult peritoneal cavity without being replenished by adult bone marrow hematopoietic stem cells (HSCs). B-1 cells are unique murine innate immune cells that are distinguished from conventional adoptive B cells (B-2 cells). B-1 cells localize in the peritoneal and pleural cavities and secrete natural antibodies without T cell help, displaying important roles in the first line of defense against various infections, atherosclerosis, and autoimmunity. It has been postulated for decades that B-1a cells are derived from fetal progenitor cells, not from adult bone marrow HSCs, based on the results of transplantation assays. We have recently reported the presence of HSC-independent B-1 progenitors in HSC-deficient embryos (PNAS 2011, 2014). Our data and others' publication showed lack of B-1a cell potential in highly purified HSCs in adult bone marrow and fetal liver, suggesting that HSC-independent B-1 progenitors are produced somewhere in the mouse embryo and contribute to producing B-1 cell pool that persists to postnatal life. Our aim is to identify the main source of HSC-independent B-1 progenitor cells and evaluate its real contribution to postnatal B-1 cell pool, utilizing various lineage tracing mouse models and transplantation assays with hematopoietic progenitors and hemogenic endothelial cells. Another important question that has not been resolved for decade is how B-1a cells are maintained without being replenished by adult bone marrow HSCs. We hypothesize that one of the polycomb proteins, Bmi1 plays a role in self-renewal capacity of mature B-1a cells in the adult peritoneal cavity. Using B cell lineage specific Bmi1 deletion, we are evaluating the B-1a cell number and their self-renewal ability upon transplantation. Comparing RNA expression profiles between wild type and Bmi1 deleted B-1a cells, we are trying to identify target genes of Bmi1 in B-1a cell self-renewal ability. We are also evaluating fat associated lymphoid clusters (FALCs) as a niche for B-1 cells in the peritoneal cavity if microenvironment is altered in Bmi1-/- mice. With knowledge obtained from above projects, we are developing a culture system to produce B-1 cells from mouse ES cells and human iPS cells in vitro. Since B-1 cells are not replenished by adult HSCs after transplantation, producing B-1 cells in vitro might open a path of cell therapy for immunocompromised patients after bone marrow transplantation.
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