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

Feb 23, 2008Stem cells (Dayton, Ohio)

Bone marrow cells produce carboxypeptidase M that trims stromal cell factor-1alpha, possibly affecting stem cell movement

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Abstract

CPM transcript is expressed by various hematopoietic and stromal cells, including bone marrow and mobilized peripheral blood CD34(+) cells.

Granulocyte-colony-stimulating factor (G-CSF) significantly increases CPM expression at both gene and protein levels in mononuclear and polymorphonuclear cells.
Recombinant CPM rapidly cleaves full-length SDF-1alpha, removing its C-terminal lysine and producing des-lys SDF-1alpha.
Treatment with CPM reduces the in vitro chemotaxis of hematopoietic stem/progenitor cells (HSPC).
The reduced chemotaxis effect is preserved when CPM is treated with the carboxypeptidase inhibitor dl-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid.
Cleavage of SDF-1alpha by CPM may attenuate chemotactic responses and could aid in G-CSF-induced mobilization of HSPC from bone marrow.

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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)-1alpha, 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-1alpha (1-68) rapidly, removing the C-terminal lysine and yielding des-lys SDF-1alpha (1-67). We demonstrated that such CPM treatment of SDF-1alpha 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-1alpha by CPM leads to attenuated chemotactic responses and could facilitate G-CSF-induced mobilization of HSPC from BM to peripheral blood.

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

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