Tsvee Lapidot: Dynamic Interactions between the Nervous and Immune Systems with the Microenvironment, Regulate Normal and Leukemic Human Stem Cells

Dynamic Interactions between the Nervous and Immune Systems with the Microenvironment, Regulate Normal and Leukemic Human Stem Cells

Tsvee Lapidot Weizmann Institute of Science, Rehovot, Israel Tsvee.Lapidot@weizmann.ac.il

Functional, preclinical NOD/SCID mice transplantation models for normal and leukemic human stem cells, revealed that homing and repopulation are dependent on SDF-1/CXCR4 interactions. Stem cell migration is a tightly regulated process, involving bone turnover, cytokines, chemokines, adhesion molecules and proteolytic enzymes. The roles of CD44, MT1-MMP, RECK, in human stem cell migration, and G-CSF induced mobilization and HGF/c-Met and ROS production will be discussed. Immature human CD34+ cells dynamically express dopamine and epinephrine receptors and inflammatory, myeloid cytokines such as G-CSF increase catecholaminergic receptor expression in order to facilitate leukocyte production and trafficking. This up regulation activates the progenitor cells in response to stimulation by the neurotransmitters and induces their motility and proliferation via Wnt signaling. Human AML stem and progenitor cells also functionally express neurotransmitter receptors which regulate their motility and development. Thus, regulation of leukocyte production and trafficking by stem cells in the BM reservoir is dynamic and involves mutual, reciprocal interactions between the nervous and immune systems with the stromal microenvironment throughout the body. Stimulations with the cytokine bFGF induce proliferation and self renewal of murine stem cells via the JAK/STAT pathway and also promote proliferation of human myeloid leukemia cells and inhibition of their differentiation via ROS inhibition. Finally, while various types of bone marrow stromal cells including osteoblasts, endothelial, reticular and nestin+ cells were identified as stem cell niche supporting cells, in addition to osteoclasts, we will discuss preliminary results on bone marrow Mac-1+/CD45+ dendritic cells which regulate hematopoietic stem and progenitor cells.