The overall objective of this project is to define how macrophages regulate the function of the marrow microenvironment and determine in what manner this function is compromised in disease states associated with hematopoietic failure. The studies proposed are based on the premise that normal stem cells fail to regenerate the hematopoietic system in diseases like myelodysplasia (MDS), myelofibrosis (MF), or aplastic anemia (AA) because the microenvironment is either nonsupportive or suppressive. Since in most cases, particularly MDS and MF, which are stem cell diseases, the stromal cells of the microenvironment (ME) should be normal, altered ME function may be hypothetically attributed to abnormal stem cell-derived macrophage known to play a critical but poorly defined role in ME function. To date, dissecting the role of the various cellular components in ME regulation has proven elusive, primarily due to the complex nature of the primary stromal cultures used for study. However, the recent development of cloned human stromal cell lines provides an opportunity to define specific cell-cell interactions. Studies using one such line, designated HS23, have shown that normal CD14+ cells induce the expression of cytokines by stromal cells via IL-1 secretion. Additional studies show that CD14+ cells from MDS patients secrete significantly less IL-1, suggesting that abnormal (Mphi) from MDS patients may compromise ME function. In this application, stromal cell lines will be used together with purified populations of M phi to define the molecular basis and consequence of normal Mphi-stromal cell interactions. Comparing results obtained from normal cells with those obtained from patients with MDS, MF, or AA, it will be possible to test the hypothesis that patient Mphi can compromise ME function. Once abnormal Mphi populations have been identified, they will be compared to normal Mphi for differential gene expression. The studies proposed should define the molecular basis of both normal and abnormal Mo- stromal interactions, thereby contributing to our understanding of marrow failure and the eventual development of more effective therapy.
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