Hematopoietic Microenvironments

Bone marrow and thymus appear to be unique in providing microenvironment factors necessary for the development of the full array of functionally immunocompetent cells (Landreth 1993; Melchers 1997; Shortman et al. 1998). The microenvironment of the bone marrow, in particular, has been the focus of considerable attention in recent years (Lichtman 1984; Collins and Dorshkind 1987; Kierney and Dorshkind 1987; Landreth and Dorshkind 1988; Dorshkind and Landreth 1992). This microenvironment is functionally composed of fibroblastic stromal cells, endothelial cells, and macrophages. However, most unique hematopoietic functions have been assigned to the fibroblastic stromal cells.

Fibroblastic bone marrow stromal cells are the best characterized element of the hematopoietic microenvironment and are known to produce an array of cytokines that regulate the tempo of differentiation, maturation, and migration of hematopoietic cells. This same set of cytokines appears to be active in the thymus as well, suggesting that the origin of bone marrow and thymic mesenchymal stromal elements may be related (Chagraoui et al. 2003). Bone marrow stromal cells are required for establishing long-term bone marrow cultures in vitro (Dexter and Lajtha 1974; Whitlock and Witte 1987; Dorshkind and Landreth 1997) and the absence or failure of stromal cell function is known to result in failure of hematopoietic cells to survive in vivo. The regulatory role proposed for the bone marrow hematopoietic microenvironment in maintaining the continual production of leukocytes required for sustained immunocompetence has led to the proposal that exposure to toxic substances may affect production of hematolymphoid cells by damaging this stromal microen-

vironment (Mudry et al. 2000; Banfi et al. 2001). This form of indirect hematotox-icity is intriguing and currently under investigation in a number of laboratories.

The hematopoietic microenvironment is characterized by the expression of adhesion molecules and cytokines, which are both produced by stromal cells (Dorshkind, 1990; Dorshkind and Landreth 1992). Adhesion contacts with stromal cells are known to contribute to the regulation of hematopoiesis and cellular adhesion molecules fibronectin, CD44, and VCAM-1, which appear to be particularly important in this respect (Kincade et al. 1989; Hahn et al. 2000). This binding involves stimulation of cell signaling cascades in both hematopoietic cells and stromal cells (Yamada and Geiger 1997). Cytokines produced by stromal cells regulate hemato-poietic cell proliferation and differentiation and include GM-CSF, G-CSF, M-CSF, IL-5 IL-7, c-kit-ligand, SDF, and IGF-1 (Namen et al. 1998; Kierney and Dorshkind 1987; Billips et al. 1992; Landreth et al. 1992; Hogan et al. 2000). Changes within the hematopoietic microenvironment resulting in alterations in cytokine production or adhesion molecule expression can alter the homeostasis of blood cell development.

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