Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche

Colmone, Angela; Sipkins, Dorothy A.

doi:10.1016/j.trsl.2007.09.003

Cited by 33 publications

(36 citation statements)

References 71 publications

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“…Using PECAM-1 labeling, we found that injected LSKCD34 Ϫ hematopoietic cells are associated, 5 hours after injection, with vascular structures, an association also detected 1 hour after injection of CD34 ϩ human hematopoietic cells in an SCID mouse. 33 As the vascular network is in close proximity to the endosteal surface in the femoral head but not in the femoral diaphysis, 14 this result extended the recent in vivo imaging of homing of transplanted HSCs in perivascular/periendosteal niches of the mouse calvarium 9 to long bones. Proliferation of transplanted LSKCD34 Ϫ hematopoietic cells could be detected 2 days after injection as measured by the decreased of CFSE fluorescence of these cells.…”

supporting

confidence: 60%

In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution

Lewandowski¹,

Barroca

Ducongé

et al. 2010

Blood

114

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IntroductionOne of the aims of regenerative medicine is to repair or restore functional organs by engrafting adult or fetal somatic stem cells into a damaged tissue. These cells, present in most self-renewing tissues, such as skin, intestine, and the hematopoietic system, can be purified, expanded ex vivo, and then used for reconstitution of damaged tissues. 1,2 Many major advances have been achieved in purification and ex vivo amplification of somatic stem cells, 1,3 but few data are available on the prerequisites that will enhance their in vivo biologic activities. New methods to improve the efficiency of bone marrow transplantation and, more generally, reconstitution of damaged tissues by somatic stem cells, depend on tracking of stem cells injected into the animal and thus on the development of imaging strategies that reveal the recruitment, homing, and initial proliferation of these injected somatic stem cells in the context of a living body.The best-characterized mammalian adult somatic stem cells are the hematopoietic stem cells (HSCs) 4,5 whose maintenance and development in the bone marrow are dependent on the HSC niche through niche-regulating pathways. 6 HSCs can be purified close to homogeneity, 7 and a single HSC can produce lifelong complete hematopoietic reconstitution of a lethally irradiated recipient mouse. 4 Many adhesion molecules, signaling pathways, and transcription factors that regulate hematopoietic reconstitution have been characterized, and the roles of these regulatory factors have been shown in vivo using overexpression or genetic inactivation.Yet, the critical early events of recruitment to the bone marrow, homing in the bone marrow microenvironment, and initial proliferation of HSCs after transplantation into lethally irradiated mice are poorly characterized because few methods are available to study these dynamics processes at the cellular level.The early cellular events that precede hematopoietic reconstitution from a small number of HSCs cannot be studied in vitro on hematopoietic cells recovered from recipient animals and presents a demanding challenge for imaging studies as the initial signals that can be detected are very weak. Among imaging techniques, 4 can presently be used to follow the reconstitution of the hematopoietic system at the cellular level. The first technique combines local surgery for placement of a bone window that is used for fluorescent microscopy, but this technique is invasive and limited by the size of the window. 8 The second technique combines high-resolution confocal microscopy and 2-photon video imaging and has greatly improved detection of multiple fluorescent signals in a living animal. This intravital microscopy permits high-resolution imaging of small tissue volume but, in the case of hematopoietic reconstitution, is limited by the thickness of the bone. [9][10][11][12] It cannot be used to study hematopoietic reconstitution in long bones and has been used to image hematopoietic reconstitution in mouse calvarium bone marrow. The third technique ...

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supporting

confidence: 60%

In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution

Lewandowski¹,

Barroca

Ducongé

et al. 2010

Blood

114

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“…Normal hematopoietic stem cells are found in close proximity to vascular endothelium (13) and vascular endothelial cells are increasingly recognized as an important component of the normal and malignant hematopoietic microenvironments (47, 48). Our study revealed that perivascular infiltration of the liver is common in primary AML xenografts and in patients with AML (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Functional integration of acute myeloid leukemia into the vascular niche

et al. 2014

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Vascular endothelial cells are a critical component of the hematopoietic microenvironment that regulates blood cell production. Recent studies suggest the existence of functional cross-talk between hematologic malignancies and vascular endothelium. Here, we show that human acute myeloid leukemia (AML) localizes to the vasculature in both patients and in a xenograft model. A significant number of vascular tissue-associated AML cells (V-AML) integrate into vasculature in vivo and can fuse with endothelial cells. V-AML cells acquire several endothelial cell-like characteristics, including the up-regulation of CD105, a receptor associated with activated endothelium. Remarkably, endothelial-integrated V-AML shows an almost 4-fold reduction in proliferative activity compared to non-vascular associated AML. Primary AML cells can be induced to down regulate the expression of their hematopoietic markers in vitro and differentiate into phenotypically and functionally-defined endothelial-like cells. After transplantation, these leukemia-derived endothelial cells are capable of giving rise to AML. Taken together, these novel functional interactions between AML cells and normal endothelium along with the reversible endothelial cell potential of AML suggest that vascular endothelium may serve as a previously unrecognized reservoir for acute myeloid leukemia.

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“…Nalm-6 ALL cells were able to downregulate SDF1 within the SDF1-rich microdomains to outcompete normal hematopoietic stem and progenitor cells. 80 Treatment with the CXCR4 antagonist, AMD3465, was shown to inhibit stromal cell-induced pro-survival signals in AML cells. 81 In addition, treatment with AMD3465 increased the sensitivity of Flt-3-mutated AML cells to the Flt-3 inhibitor, sorafenib and induced the mobilization of AML cells into the peripheral blood, yielding a reduction in AML burden in mice following sorafenib treatment.…”

Section: Do Ecs Secrete Soluble Growth Factors That Mediate Hsc Self-mentioning

confidence: 99%

The vascular niche: home for normal and malignant hematopoietic stem cells

2011

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Hematopoietic stem cells (HSCs) are uniquely capable of selfrenewal and provision of all of the mature elements of the blood and immune system throughout the lifetime of an individual. HSC self-renewal is regulated by both intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments or 'niches' wherein HSCs reside. HSCs have been shown to reside in close association with bone marrow (BM) osteoblasts in the endosteal niche and also in proximity to BM sinusoidal vessels. An unresolved question surrounds whether the endosteal and vascular niches provide synchronous or redundant regulation of HSC fate or whether these niches provide wholly unique regulatory functions. Furthermore, while some aspects of the mechanisms through which osteoblasts regulate HSC fate have been defined, the mechanisms through which the vascular niche regulates HSC fate remain obscure. Here, we summarize the anatomic and functional basis supporting the concept of an HSC vascular niche as well as the precise function of endothelial cells, perivascular cells and stromal cells within the niche in regulating HSC fate. Lastly, we will highlight the role of the vascular niche in regulating leukemic stem cell fate in vivo. Leukemia (2012) Concept of the hematopoietic stem cell (HSC) nicheThe concept of an instructive role for the bone marrow (BM) microenvironment in regulating hematopoietic cell fate was introduced at least 50 years ago and has been validated over the past decade. 1-9 It has long been postulated that HSCs reside in specialized niches within the adult BM. [8][9][10][11][12][13][14] In addition to HSCs and their progeny, the BM comprises a rich network of osteoblasts, mesenchymal stem cells (MSCs), neuronal cells, adipocytes, sinusoidal vessels and perivascular reticular cells (Figure 1). Recently, genetic knockout studies have begun to demonstrate the functional role of specific cells within the BM microenvironment in regulating hematopoiesis. [3][4][5]7,[15][16][17][18][19][20] Interestingly, certain niches within the BM may uniquely regulate HSC homeostasis in vivo while other niches may be more relevant to HSC regeneration following injury. However, it remains unknown whether there is meaningful 'cross-talk' between distinct microenvironmental cells in regulating HSC fate in vivo. Interestingly, as early as 1961, Fliedner et al. 9 postulated that the recovery of hematopoiesis in rats following 1000 cGy total body irradiation (TBI) required the recovery of an intact vasculature. Similarly, McClugage et al. 14 used a window chamber to visualize dynamic changes in tibial BM cellularity and architecture in live rabbits. Interestingly, both studies suggested a strong association between vasculogenesis in the BM and the hematopoietic response to stress or injury. 9,14 Role of the BM osteoblast With advances in mouse genetics and microscopy, the function of the BM osteoblast in regulating hematopoiesis and HSC homeostasis has been demonstrated. 4,5,14,[21][22][23][24] Human osteoblasts were shown by Taichma...

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Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche

Cited by 33 publications

References 71 publications

In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution

In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution

Functional integration of acute myeloid leukemia into the vascular niche

The vascular niche: home for normal and malignant hematopoietic stem cells

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