Abstract
We review the murine and human microenvironment and hematopoietic stem cell niche in the context of intact bone marrow architecture in man and mouse, both in normal and in myelodysplastic syndrome marrow. We propose that the complexity of the hematopoietic stem cell niche can usefully be approached in the context of its topobiology, and we provide a model that incorporates in vitro and in vivo models as well as in situ findings from intact human marrow to explain the changes seen in myelodysplastic syndrome patients. We highlight the clinical application of the study of the bone marrow microenvironment and its topobiology in myelodysplastic syndromes.
Highlights
Topobiology, first proposed in the setting of embryonic development [1], is the principle that cellular and molecular interactions are place-dependent
Dr Morrison’s group used a model of differential depletion of stem cell factor (SCF, known as KIT-ligand) in osteoblasts, hematopoietic cells, endothelial cells and Leptin receptor (LepR)+ mesenchymal stem cells (MSCs); these authors found that hematopoietic stem cells (HSCs) were eliminated in the bone marrow of mice whose SCF had been eliminated in endothelial cells and MSCs only [29]
There has been a lot of attention paid to the role of MSCs in normal and dysplastic/leukemic hematopoiesis, in both mouse and human [86,87,88,89], The first papers that characterized MSCs in the setting of myelodysplastic syndromes (MDS) by morphology, immunophenotype and differentiation potential were published in 2005 [90] and since, more than 80 papers have been published in this field (Table 1).The first finding was related to the chromosomal abnormalities present in MSCs
Summary
Topobiology, first proposed in the setting of embryonic development [1], is the principle that cellular and molecular interactions are place-dependent. The bone marrow microenvironment is a complex topobiologic unit that orchestrates normal and, in the setting of myelodysplastic syndromes (MDS), malignant hematopoiesis. Perturbations of the microenvironment are capable of inducing myelodysplasia in mouse models, and translational studies indicate that evaluation of the microenvironment may provide novel prognostic information in myelodysplastic syndromes. In vitro methods by their nature involve loss of microenvironmental interactions; mouse models have the advantage of a tractable and intact system, which does differ in key ways from the human myelodysplastic marrow microenvironment. We review bone marrow architecture in the context of the diagnostic bone marrow biopsy in man and in wild type mouse; the murine and human microenvironment and hematopoietic stem cell niche; and clinical applications of the study of the bone marrow microenvironment in myelodysplastic syndromes
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