A study for the mechanism of negative hematopoietic regulation by bone marrow microenvironment.

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Normal hematopoiesis is characterized by a balanced interplay between hematopoietic stem cells and the cells and molecules that form the portion of the microenvironment in which blood cell production takes place. This in turn suggests that alterations in some of the elements of this microenvironment may result in abnormal production of blood cells. Bone marrow stromal cells, a heterogenous collection of mesenchymal cells that grow as an adherent layer in bone marrow culture, are an essential component of the microenvironment. In this study, the hematopoietic regulatory mechanisms of stromal cell were investigated in vitro.1) A cloned stromal cell line (LS801) was established from an myelodysplastic syndrome (MDS) refractory anemia (RA) patient by introducing recombinant SV40-adenovirus vector containing the SV40 early gene. LS801 induced an apoptotic change in hematopoietic cells in a coculture system. When hematopoietic cells were cocultured but kept separate from LS801 by a 0.45μm Mi … More llipore membrane to prevent their attachment, the action of LS801 in inducing apoptosis of hematopoietic cells was inhibited. These findings suggest that LS801 induced an apoptotic change of hematopoietic cells by producing diffusible factor(s) and via direct cellular interactions.2) A supramolecular oligomer, cyclic polylactate was isolated from the culture medium of LS801. This oligomer was found to induce apoptotic change in hematopoietic cells. The mechanism responsible for this action remains unclear, however, the activities of glycolytic enzymes of hematopoietic cells treated with this oligomer were suppressed.3) In some stromal cells originated from MDS patients induced apoptotic change of hematopoietic cells by producing TNFα. We found that the treatment with vitamin K2 suppressed the production of TNFα from these stromal cells, and hematopoiesis in culture with these stromal cells were stimulated.All these findings suggest that stromal cells possess both stimulatory and inhibitory action for the proliferation and differentiation of hematopoietic cells. Less