Abstract
Two distinct microenvironmental niches that regulate hematopoietic stem/progenitor cell physiology in the adult bone marrow have been proposed; the endosteal and the vascular niche. While extensive studies have been performed relating to molecular interactions in the endosteal niche, the mechanisms that regulate hematopoietic stem/progenitor cell interaction with bone marrow endothelial cells are less well defined. Here we demonstrate that endothelial cells derived from the bone marrow supported hematopoietic stem/progenitor cells to a higher degree than other endothelial or stromal cell populations. This support was dependant upon placental growth factor expression, as genetic knockdown of mRNA levels reduced the ability of endothelial cells to support hematopoietic stem/progenitor cells in vitro. Furthermore, using an in vivo model of recovery from radiation induced myelosuppression, we demonstrate that bone marrow endothelial cells were able to augment the recovery of the hematopoietic stem/progenitor cells. However, this effect was diminished when the same cells with reduced placental growth factor expression were administered, possibly owing to a reduced homing of the cells to the bone marrow vasculature. Our data suggest that placental growth factor elaborated from bone marrow endothelial cells mediates the regulatory effects of the vascular niche on hematopoietic stem/progenitor cell physiology.
Highlights
Hematopoietic stem cells (HSCs) are maintained, and their physiology regulated, in specialized microenvironments known as the stem cell niche [1]
It has been shown that 60% of HSCs in the adult bone marrow (BM) are in contact with sinusoidal endothelium, while only 14% are at the endosteal surface [6]
Characterization of endothelial and stromal cell cultures BM mononuclear cells (MNCs) were isolated from central marrow or endosteal marrow, and grown in either endothelial or stromal cell culture conditions
Summary
Hematopoietic stem cells (HSCs) are maintained, and their physiology regulated, in specialized microenvironments known as the stem cell niche [1]. It has been shown that 60% of HSCs in the adult BM are in contact with sinusoidal endothelium, while only 14% are at the endosteal surface [6] It is not known if direct contact with endothelial cells (ECs) in the vascular niche is required for self-renewal of HSCs as the mechanisms for the support remain relatively unknown. Previous studies examined the ability of primary adult mice ECs from non-hematopoietic organs such as heart, brain, liver, lung and kidney to support hematopoietic stem/progenitor cells (HSPC). Using in vitro co-culture assays as well as in vivo competitive repopulation assays, these studies demonstrated differences in the supportive ability of the ECs, as brain and heart ECs could expand the HSC population, while lung and liver ECs maintained the hematopoietic cells. These effects were only correlated with an expression of PTN in BM ECs
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