The Hematopoietic Microenvironment: Phylogeny and Ontogeny of the Hematopoietic Microenvironment.
Although there is no formalized area of study called phylogeny or ontogeny of the hematopoietic microenvironment, new models and molecular tools are now available for such studies. The concept of a hematopoietic microenvironment has developed from the need to answer basic questions about migration, control of proliferation and differentiation of lymphohematopoietic cells; e.g. how are cells with the same genes induced to express different sets of these genes which lead to differentiation. These questions were first approached when cells could only be identified morphologically. The ontogeny of hematopoiesis was traced from the blood islands of the embryonic yolk sac, to the fetal liver, spleen, and bone marrow. Cells with reticular morphology were associated with areas of hematopoiesis and, in the embryo, they were thought to give rise to both hematopoietic and supportive cells. In the 1960's the classic work of McCulloch, Till and Siminovitch led the study of hematopoietic precursors which have no distinctive morphological identity and are too infrequent to study microscopically. These cells were identified by their functions; e.g. colony formation in culture in the presence of certain factors, production of spleen colonies or rescue of lethally irradiated mice. Cells with these functions were also found sequentially in the yolk sac blood islands, in the aorta/mesonephros, fetal liver, spleen, and bone marrow during development. The question remained, what regulates the proliferation and differentiation of these cells and why do they home to different sites in different stages of development? Among the laboratories studying spleen colonies, a controversy arose as to whether differentiation decisions were stochastic or induced by extra cellular factors. Dexter and Greenberger developed the long-term bone marrow culture system which has aided in studying the roles of factors such as cell-cell contact and extracellular matrix in hematopoietic differentiation. The molecular identification of ligand/receptor pairs such as ckit and KL as well as transactivating factors that control whole sets of lineage related genes such as the GATAs and Ikaros, may lead to clarification of the stochastic versus induced differentiation issue. Chimeric bird and frog embryos and analysis of mutations effecting hematopoiesis in frogs and zebrafish have helped to trace the earliest hematopoietic development in the embryo and to determine what influences it. The identification of genes that alter development of hematopoiesis opens the possibility of comparing microenvironmental control mechanisms in various present day organisms and relating these to evolutionary events. Many basic questions relevant to the interaction between hematopoietic cells and their microenvironment can be addressed by studying "simple" organisms in which the answers may be more easily determined than in mice or humans. Examples of possibly useful organisms, range from the teliosts such as zebrafish to algae such as Volvox, a two cell organism, to Dictyostelium which change from 1 to many cell types and in the process, migrate, adhere and differentiate.
Boggs
SALLIE S.
SS
Department Radiation Oncology, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh PA 15261.