Orit Kollet

The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m null mice

Hematopoietic stem cells are identified based on their functional ability to migrate via the blood circulation of transplanted recipients, to home to the host bone marrow and to durably repopulate this organ with high levels of maturing myeloid and lymphoid cells. While a small pool of undifferentiated stem cells with the potential to repeat the entire process in serially transplanted recipients is maintained within the bone marrow, maturing cells are continuously released into the circulation. In recent years pre-clinical, functional in vivo models for human stem cells have been developed, using immune-deficient mice or pre-immune, fetal sheep as recipients. The mechanism of human stem cell migration, homing and repopulation in transplanted immune-deficient NOD/SCID and NOD/SCID/B2mnull mice as well as the accessory mediators that facilitate these processes, will be reviewed. In particular, the essential roles of the chemokine SDF-1 and its receptor CXCR4 which mediate and regulate stem cell homing and repopulation will be discussed.

Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors.

The role of corticosterone (Cort), the immune system’s major stress hormone, in the regulation of hematopoietic stem and progenitor cells (HSPCs) and their dynamic bone marrow (BM) microenvironment is currently unknown. We report that corticotropin-releasing factor receptor 1 (CRFR1) mutant mice with chronically low Cort levels showed aberrant HSPC regulation, having higher HSPC numbers and upregulation of the chemokine CXCL12, phenotypes that were restored by Cort supplementation. Expanded stromal progenitors known to support HSPCs were also observed in these low-Cort-containing mice. A similar phenotype was induced in wild-type (WT) mice by Metyrapone, a Cort synthesis inhibitor. Conversely, high Cort exposure induced HSPC apoptosis, reduced long-term BM repopulation and decreased stromal progenitor cell numbers. We documented circadian oscillations of Cort in WT BM but not in CRFR1 mutant mice, leading to diminished circadian BM CXCL12 fluctuations and increased number of circulating HSPCs in these mice. Finally, low Cort induced expansion of stromal progenitors, CXCL12 expression, HSPC proliferation and BM repopulation capacity, involving Notch1 signaling. This was associated with upregulation of the Notch ligand, Jagged1, in BM myeloid cells. Our results suggest that daily physiologic Cort oscillations are critical for balanced HSPC proliferation and function involving Notch1 signaling and their supportive BM microenvironment.

MicroRNA-155 promotes G-CSF-induced mobilization of murine hematopoietic stem and progenitor cells via propagation of CXCL12 signaling

MicroRNA-155 promotes G-CSF-induced mobilization of murine hematopoietic stem and progenitor cells via propagation of CXCL12 signaling