Studies of progenitor cell transendothelial migration: effects of cytokine mediators, signal transduction inhibitors, and gelatinases

Jane L. Liesveld, Karen Resell, Alan Smith, Jeffrey Lancet, Camille N. Abboud

Research output: Contribution to journalArticle

Abstract

It has been shown previously that CD34+ progenitors and leukemic blast cells migrate through endothelial monolayers in response to numerous cytokines and chemokines with the greatest response noted to stroma derived factor-1 alpha (SDF-la). We have further explored the mechanism of this transmigration via inhibitors or modulators of various elements in this in vitro system. Human umbilical vein endothelial cells (HuVECs) and marrow stromal cells produce both gelatinases A and B, and TNF and IL-1 are known to increase their production of these gelatinases. Addition of TNF-a or IL-1 βto HuVEC layers did not increase CD34+ cell transmigration, however, addition of ImM of the metalloproteinase inhibitor, 1,10-phenanthroline to the endothelial layers completely inhibited the transmigration of marrow CD34+ cells in response to SDF-la (100 ng/ml), suggesting gelatinase involvement in this process. Exposure of CD34+ cells alone to this inhibitor did not completely block transmigration. The migration of normal CD34+ cells and AML blasts in response to 100 ng/ml SDF-la was inhibited by exposure to pertussis toxin, a G-protein inhibitor, from concentrations of 10 ng/ml to 500ng/ml, and the protein kinase C inhibitor staurosporine at 10 ng/ml to 1 Hg/ml also inhibited baseline and chemokine stimulated transmigration of AML blasts. The incremental transmigration in response to chemokines was partially inhibited by EGTA, 10 mM to ImM. Cytochalasin B, 2 \M to 200 [iM completely inhibited AML blast transmigration at higher doses. The migration of AML blasts through a fibronectin-coated transwell membrane was increased in response to various chemokines as compared to control conditions but the incremental increase in response to chemokines and cytokines was not as great as seen with HuVEC monolayer transmigration. These studies underscore the contribution of multiple cellular and matrix components and signal transduction pathways in the transendothelial migration of normal and leukemic cell progenitors; a process which has importance for progenitor cell homing to and egress from microenvironmental niches. Studies of the mechanisms of these complex cell-cell and cellmatrix interactions may elucidate ways to manipulate the pathologic migration potential of leukemic cells.

Original languageEnglish
Pages (from-to)151b
JournalBlood
Volume96
Issue number11 PART II
StatePublished - Dec 1 2000
Externally publishedYes

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