Hierarchy of immature hematopoietic cells related to blood flow and niche

Abstract

Steady-state hematopoiesis in adult bone marrow requires the maintenance of a small pool of hematopoietic stem cells (HSCs) by self-renewing symmetric division. HSCs can be divided into potent rarely dividing HSCs which function as long-term reserve and more proliferative HSCs which contribute to maintaining the blood and immune cell pool. Extrinsic instructions provided by unique microenvironments (niches) regulate the fate of individual HSCs and progenitors. This review discusses the latest findings in respect to the organization and function of these niches. It has recently emerged that mesenchymal stem cells, various osteoblastic progenitors and sinusoidal endothelial cells all critically regulate HSCs within niches. Each of these niche cells expresses different arrays of signaling proteins which differentially regulate HSCs and progenitors. HSCs have been reported in two types of niches. However, as osteoblastic/mesenchymal niches and perivascular niches overlap anatomically, this makes the dichotomy between osteoblastic niches for quiescent HSCs and endothelial niches for more proliferative HSCs a too simplistic model. Indeed local blood perfusion in a niche alone can functionally separate HSC populations. The fate of each individual HSC is likely to be the result of the unique balance between signals elicited by proteins expressed by mesenchymal/osteoblastic progenitors, sinusoidal endothelial cells and physicochemical cues such as local blood perfusion and hypoxia in each individual niche. More sophisticated three-dimensional fluorescence microscopy techniques on whole mount bone fragments should provide new insights in the spatial organization of niches relative to bone and microcirculation in the bone marrow.