G-CSF induced progenitor mobilization in mice with PIGA- blood cells.

OBJECTIVE: In patients with paroxysmal nocturnal hemoglobinuria (PNH) a proportion of blood cells are deficient in glycosyl phosphatidylinositol (GPI) anchored proteins due to a mutation in the PIGA gene. Previous studies showed that in PNH the majority of circulating early progenitor cells were normal but after G-CSF were mainly, of the PNH phenotype. This suggested that GPI-linked proteins contribute to the regulation of progenitor trafficking from bone marrow to peripheral blood. METHODS: To test this hypothesis we studied progenitor cells in bone marrow, spleen, and peripheral blood in response to G-CSF in mice genetically engineered to have a proportion of blood cells deficient in GPI-linked proteins (LF mice). RESULTS: In contrast to humans, LF and wild-type mice have comparable numbers of progenitor cells in bone marrow, spleen, and peripheral blood. Similarly, in LF mice the proportion of PIGA- progenitor cells in peripheral blood corresponds the proportion of PIGA- progenitor cells measured in bone marrow and spleen. After G-CSF the number of circulating progenitors significantly increased but the proportion of PIGA- cells remained the same in peripheral blood,bone marrow, and spleen. CONCLUSIONS: Our data indicate that under basal laboratory conditions the lack of GPI-linked protein does not cause a retention of progenitor cells in the bone marrow. This implies that the preferential circulation of normal progenitor cells in patients with PNH requires an additional component that most likely is provided by the altered microenvironment of the underlying bone marrow failure.

Cytokines and hematopoietic stem cell mobilization.

Hematopoietic stem cell transplantation (HSCT) has become the standard of care for the treatment of many hematologic malignancies, chemotherapy sensitive relapsed acute leukemias or lymphomas, multiple myeloma; and for some non-malignant diseases such as aplastic anemia and immunodeficient states. The hematopoietic stem cell (HSC) resides in the bone marrow (BM). A number of chemokines and cytokines have been shown in vivo and in clinical trials to enhance trafficking of HSC into the peripheral blood. This process, termed stem cell mobilization, results in the collection of HSC via apheresis for both autologous and allogeneic transplantation. Enhanced understanding of HSC biology, processes involved in HSC microenvironmental interactions and the critical ligands, receptors and cellular proteases involved in HSC homing and mobilization, with an emphasis on G-CSF induced HSC mobilization, form the basis of this review. We will describe the key features and dynamic processes involved in HSC mobilization and focus on the key ligand-receptor pairs including CXCR4/SDF1, VLA4/VCAM1, CD62L/PSGL, CD44/HA, and Kit/KL. In addition we will describe food and drug administration (FDA) approved and agents currently in clinical development for enhancing HSC mobilization and transplantation outcomes.