Author Affiliations

  1. Ombretta Salvucci1,
  2. Kan Jiang1,
  3. Paola Gasperini1,
  4. Dragan Maric2,
  5. Jinfang Zhu3,
  6. Shuhei Sakakibara1,
  7. Georgina Espigol-Frigole1,
  8. Shushang Wang4 and
  9. Giovanna Tosato1
  1. 1Laboratory of Cellular Oncology, CCR, NCI, NIH, Bethesda MD, USA
  2. 2Laboratory of Neurophysiology, NINDS, NIH, Bethesda MD, USA
  3. 3Laboratory of Immunology, NIAID, NIH, Bethesda MD, USA
  4. 4Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
  1. Correspondence: Ombretta Salvucci, Laboratory of Cellular Oncology, CCR, NCI, NIH; Building 37, Room 4124, Bethesda, MD 20892 USA. Phone: international +1.301.5949586. Fax: international +1.301.5949585. E-mail salvucco{at}mail.nih.gov
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Abstract

Background Mobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs.

Design and Methods We analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells.

Results We show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor.

Conclusions Our results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.

  • Received October 12, 2011.
  • Revision received December 15, 2011.
  • Accepted January 2, 2012.
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