Influences of vascular niches on hematopoietic stem cell fate

International Journal of Hematology, Apr 2014

The fate decision of hematopoietic stem cells (HSCs), quiescence, proliferation or differentiation, is uniquely determined by functionally specialized microenvironments defined as the HSC niches. However, whether quiescence and proliferation of HSCs are regulated by spatially distinct niches is unclear. Although various candidate stromal cells have been identified as potential niche cells, the spatial localization of quiescent HSCs in the bone marrow remains controversial. In our recent study, we have established whole-mount confocal immunofluorescence techniques, which allow us to precisely assess the localization of HSCs and their relationships with stromal structures. Furthermore, we have assessed the significance of these associations using a computational simulation. These novel analyses have revealed that quiescent HSCs are specifically associated with small caliber arterioles, which are predominantly distributed in the endosteal bone marrow while the associations with sinusoidal vessels or osteoblasts are not significant. Physical ablation of the arteriolar niche causes the shift of HSC localization to sinusoidal niches, where HSCs are switched into non-quiescent status. This new imaging analyses together with previous studies suggest the presence of spatially distinct vascular niches for quiescent and non-quiescent (proliferating) HSCs in the bone marrow.

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Influences of vascular niches on hematopoietic stem cell fate

Yuya Kunisaki 0 1 2 3 Paul S. Frenette 0 1 2 3 0 Y. Kunisaki P. S. Frenette Department of Medicine, Albert Einstein College of Medicine , Bronx, NY 10461, USA 1 Y. Kunisaki P. S. Frenette Department of Cell Biology, Albert Einstein College of Medicine , Bronx, NY 10461, USA 2 Y. Kunisaki P. S. Frenette (&) Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research , Bronx, NY 10461, USA 3 Present Address: Y. Kunisaki (&) Department of Medicine and Biosystemic Science, Kyushu University , Fukuoka, Fukuoka 812-8582, Japan The fate decision of hematopoietic stem cells (HSCs), quiescence, proliferation or differentiation, is uniquely determined by functionally specialized microenvironments defined as the HSC niches. However, whether quiescence and proliferation of HSCs are regulated by spatially distinct niches is unclear. Although various candidate stromal cells have been identified as potential niche cells, the spatial localization of quiescent HSCs in the bone marrow remains controversial. In our recent study, we have established whole-mount confocal immunofluorescence techniques, which allow us to precisely assess the localization of HSCs and their relationships with stromal structures. Furthermore, we have assessed the significance of these associations using a computational simulation. These novel analyses have revealed that quiescent HSCs are specifically associated with small caliber arterioles, which are predominantly distributed in the endosteal bone marrow while the associations with sinusoidal vessels or osteoblasts are not significant. Physical ablation of the - arteriolar niche causes the shift of HSC localization to sinusoidal niches, where HSCs are switched into non-quiescent status. This new imaging analyses together with previous studies suggest the presence of spatially distinct vascular niches for quiescent and non-quiescent (proliferating) HSCs in the bone marrow. Hematopoietic stem cells Quiescence Hematopoietic stem cells (HSCs) maintain hematopoietic homeostasis through lifelong replenishment of all blood cell lineages by a finely tuned orchestration of self-renewal and differentiation controlled by specific cellular and molecular microenvironments defined as niches [1]. The niche concept has been validated by numerous studies since Schofield postulated its presence in 1978 [2]. Most of HSCs divide infrequently and are quiescent in the niche [3]. However, they are reversibly activated in response to hematopoietic stresses [4]. Cell cycle quiescence is a key behavior of stem cells, which protects them from being exhausted by exogenous insults [5] and is also assumed to prevent them from acquiring genetic mutations that potentially result in consequent malignant transformations [6]. Although quiescence and proliferation of HSCs are thought to be regulated by their microenvironments, it remains unclear whether and if so how spatially distinct niches control cell cycle status. The identification of cellular constituents of the HSC niche has recently been the subject of intense investigations. Osteoblasts have been proposed to promote HSC quiescence via direct contact [7] and the secretion of angiopoietin-1 [8] or osteopontin [9, 10]. On the other hand, an emerging role of the bone marrow vasculature has recently gained support and interest [11] as other studies have found that most HSCs are localized adjacent to blood vessels (sinusoids), near perivascular cell populations characterized as CXCL12-abundant reticular (CAR) cells [12, 13], Nestin? mesenchymal stem cells [14], and Leptin receptor (LEPR)? cells [15]. Based on the previous studies, a prevalent unifying interpretation of the literature has been that the osteoblastic and vascular niches could confer distinct microenvironments promoting HSC quiescence and proliferation, respectively. However, this popular concept has not been supported by rigorous analyses. Recent studies further have reported that endothelial cells and perivascular stromal cells are sources of the factors such as CXCL12 and stem cell factor (SCF), known to be essential for HSC retention and maintenance [1416]. Series of studies also have shown that genetic deletion of the factor, CXCL12, in osteoblasts [17] and ablation of osteoblasts (David T. Scadden personal communication) affect lymphoid-committed progenitors rather than HSCs. On the other hand, the proximity of HSCs to sinusoidal vessels, which has been reported in many previous studies, might be biased by the abundance and dense network of sinusoids in the bone marrow. The relationship between HSCs and arteries has been well documented in the emergence of HSCs during development as definitive hematopoiesis is beginning in the aortagonadmesonephros (AGM) region [18]. However, it has been unknown whether arteries play specific roles for HSCs in adult bone marrow. To address these issues, we have established a wholemount immunofluorescence imaging technique in which the thre (...truncated)


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Yuya Kunisaki, Paul S. Frenette. Influences of vascular niches on hematopoietic stem cell fate, International Journal of Hematology, 2014, pp. 699-705, Volume 99, Issue 6, DOI: 10.1007/s12185-014-1580-4