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THE STEM CELL NICHE

Carboxypeptidase M Expressed by Human Bone Marrow Cells Cleaves the C-Terminal Lysine of Stromal Cell-Derived Factor-1: Another Player in Hematopoietic Stem/Progenitor Cell Mobilization?

^aResearch and Development, Canadian Blood Services, Edmonton, Alberta, Canada;
^bDepartment of Medicine, University of Alberta, Edmonton, Alberta, Canada;
^cLaboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium

Key Words. Carboxypeptidase M • Stromal cell-derived factor-1 • CXCR4 • Granulocyte-colony-stimulating factor • Mobilization • Bone marrow

Correspondence: Anna Janowska-Wieczorek, M.D., Ph.D., Department of Medicine, Faculty of Medicine and Dentistry, CBS Building, 8249–114th Street, Edmonton, Alberta T6G 2R8, Canada. Telephone: 780-431-8761; Fax: 780-702-8622; e-mail: anna.janowska{at}blood.ca

Received August 30, 2007; accepted for publication February 15, 2008.
First published online in STEM CELLS EXPRESS   February 21, 2008.



Carboxypeptidase M (CPM) is a membrane-bound zinc-dependent protease that cleaves C-terminal basic residues, such as arginine or lysine, from peptides/proteins. We examined whether CPM is expressed by hematopoietic and stromal cells and could degrade stromal cell-derived factor (SDF)-1, a potent chemoattractant for hematopoietic stem/progenitor cells (HSPC). We found that (a) CPM transcript is expressed by bone marrow (BM) and mobilized peripheral blood CD34⁺ cells, myeloid, erythroid, and megakaryocytic cell progenitors, mononuclear cells (MNC), polymorphonuclear cells (PMN), and stromal cells, including mesenchymal stem cells; and that (b) granulocyte-colony-stimulating factor (G-CSF) significantly increases its expression at the gene and protein levels in MNC and PMN. Moreover, we found that recombinant CPM cleaves full-length SDF-1 (1–68) rapidly, removing the C-terminal lysine and yielding des-lys SDF-1 (1–67). We demonstrated that such CPM treatment of SDF-1 reduced the in vitro chemotaxis of HSPC, which, however, was preserved when the CPM was exposed to the carboxypeptidase inhibitor DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid. Thus, we present evidence that CPM is expressed by cells occurring in the BM microenvironment and that the mobilizing agent G-CSF strongly upregulates it in MNC and PMN. We suggest that cleavage of the C-terminal lysine residue of SDF-1 by CPM leads to attenuated chemotactic responses and could facilitate G-CSF-induced mobilization of HSPC from BM to peripheral blood.

Disclosure of potential conflicts of interest is found at the end of this article.