Publications

Preprints

2009

Blood-forming stem cells are nervous: Direct and indirect regulation of immature human CD34⁺ cells by the nervous system

Kalinkovich A., Spiegel A., Shivtiel S., Kollet O., Jordaney N., Piacibello W. & Lapidot T. (2009) Brain Behavior And Immunity. 23, 8, p. 1059-1065 Abstract

The nervous system regulates immunity through hormonal and neuronal routes as part of host defense and repair mechanism. Here, we review the emerging evidence for regulation of human hematopoietic stem and progenitor cells (HSPC) by the nervous system both directly and indirectly via their bone marrow (BM) niche-supporting stromal cells. Functional expression of several neurotransmitter receptors was demonstrated on HSPC, mainly on the more primitive CD34⁺/CD38^-/low fraction. The myeloid cytokines, G-CSF and GM-CSF, dynamically upregulate neuronal receptor expression on human HSPC. This is followed by an increased response to neurotransmitters, leading to enhanced proliferation and motility of human CD34⁺ progenitors, repopulation of the murine BM and their egress to the circulation. Importantly, recent observations showed rapid mobilization of human HSPC to high SDF-1 expressing ischemic tissues of stroke individuals followed by neoangiogenesis, neurological and functional recovery. Along with decreased levels of circulating immature CD34⁺ cells and SDF-1 blood levels found in patients with early-stage Alzheimer's disease, these findings suggest a possible involvement of human HSPC in brain homeostasis and thus their potential clinical applications in neuropathology.

MT1-MMP and RECK are involved in human CD34⁺ progenitor cell retention, egress, and mobilization

Vagima Y., Avigdor A., Goichberg P. et al. (2009) Journal of Clinical Investigation. 119, 3, p. 492-503 Abstract

The mechanisms governing hematopoietic progenitor cell mobilization are not fully understood. We report higher membrane type 1-MMP (MT1-MMP) and lower expression of the MT1-MMP inhibitor, reversioninducing cysteine-rich protein with Kazal motifs (RECK), on isolated circulating human CD34⁺ progenitor cells compared with immature BM cells. The expression of MT1-MMP correlated with clinical mobilization of CD34⁺ cells in healthy donors and patients with lymphoid malignancies. Treatment with G-CSF further increased MT1-MMP and decreased RECK expression in human and murine hematopoietic cells in a PI3K/ Akt-dependent manner, resulting in elevated MT1-MMP activity. Blocking MT1-MMP function by Abs or siRNAs impaired chemotaxis and homing of G-CSF-mobilized human CD34⁺ progenitors. The mobilization of immature and maturing human progenitors in chimeric NOD/SCID mice by G-CSF was inhibited by anti-MT1-MMP treatment, while RECK neutralization promoted motility and egress of BM CD34⁺ cells. BM c-kit⁺ cells from MT1-MMP-deficient mice also exhibited inferior chemotaxis, reduced homing and engraftment capacities, and impaired G-CSF-induced mobilization in murine chimeras. Membranal CD44 cleavage by MT1-MMP was enhanced following G-CSF treatment, reducing CD34⁺ cell adhesion. Accordingly, CD44-deficient mice had a higher frequency of circulating progenitors. Our results reveal that the motility, adhesion, homing, and mobilization of human hematopoietic progenitor cells are regulated in a cell-autonomous manner by dynamic and opposite changes in MT1-MMP and RECK expression.

[All authors]