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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4496-4502.
Prepublished online as a Blood First Edition Paper on March 2, 2004; DOI 10.1182/blood-2004-01-0256.
Submitted January 21, 2004
Accepted February 16, 2004
Human Marrow Stromal Cells Activate Monocytes to Secrete Osteopontin, which Down-regulates Notch1 Gene Expression in CD34+ Cells
Mineo Iwata, Norihiro Awaya, Lynn Graf, Christoph Kahl, and Beverly Torok-Storb*
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
* Corresponding author; email: btorokst{at}fhcrc.org.
The hematopoietic microenvironment, approximated in vitro by long-term marrow cultures (LTC), consists of both nonhematopoietic-derived stromal elements and hematopoietic-derived monocyte/macrophages. To better understand the consequences of monocyte-stroma interactions we compared gene expression profiles of CD14+ peripheral blood monocytes and HS-27a stromal cells cultured alone and together in co-cultures. Results from 7 separate experiments revealed 22 genes were significantly up or down regulated in the co-cultures, with osteopontin (OPN) up-regulated >15 fold. The microarray OPN data was confirmed by Northern blot, real time PCR, and by detection of OPN protein. High levels of OPN gene expression were also detected in 2-3 week old primary LTC. Using transwells we determined that stromal cells were secreting a factor that upregulated OPN gene expression in CD14+ cells. When CD34+ cells were cultured in the presence of purified OPN, tyrosine phosphorylation of a 34-kd molecule was increased 2-3 fold, an effect that was diminished in the presence of an OPN neutralizing monoclonal antibody. In addition, Notch1 gene expression was decreased 5-fold in OPN treated CD34+ cells. We conclude that interactions between stroma and monocytes can result in activities that limit the role of Notch signaling in hematopoietic regulation.
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